Method of treating gram-negative bacterial infection by administration of bactericidal/permeability-increasing (BPI) protein product and antibiotic

ABSTRACT

The present invention relates to methods and compositions for treating gram-negative bacterial infections, using BPI protein products. Co-treatment, or concurrent administration, of BPI protein product with an antibiotic in treatment of gram-negative bacterial infections improves the therapeutic effectiveness of the antibiotic, including increasing antibiotic susceptibility of gram-negative bacteria and reversing resistance of the bacteria to antibiotics.

This is a continuation-in-part of U.S. application Ser. No. 08/273,401filed Jul. 11, 1994, now abandoned, which is a continuation-in-part ofU.S. application Ser. No. 08/125,651 filed Sep. 22, 1993, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates generally to methods and compositions fortreating gram-negative bacterial infections, and more specifically tothe use of bactericidal/permeability-increasing protein (BPI) proteinproducts for co-treatment of such infections with an antibioticsubstance. Co-treatment with BPI protein products can improve thetherapeutic effectiveness of antibiotics in gram-negative bacterialinfections, increase the susceptibility of gram-negative organisms toantibiotics, and reverse resistance of gram-negative organisms toantibiotics.

BPI is a protein isolated from the granules of mammalianpolymorphonuclear leukocytes (PMNs or neutrophils), which are bloodcells essential in the defense against invading microorganisms. HumanBPI protein has been isolated from PMNs by acid extraction combined witheither ion exchange chromatography [Elsbach, J. Biol. Chem., 254:11000(1979)] or E. coli affinity chromatography [Weiss, et al., Blood, 69:652(1987)]. BPI obtained in such a manner is referred to herein as naturalBPI and has been shown to have potent bactericidal activity against abroad spectrum of gram-negative bacteria. The molecular weight of humanBPI is approximately 55,000 daltons (55 kD). The amino acid sequence ofthe entire human BPI protein and the nucleic acid sequence of DNAencoding the protein have been reported in FIG. 1 of Gray et al., J.Biol. Chem., 264:9505 (1989), incorporated herein by reference. The Grayet al. amino acid sequence is set out in SEQ ID NO: 69 hereto.

BPI is a strongly cationic protein. The N-terminal half of BPI accountsfor the high net positive charge; the C-terminal half of the moleculehas a net charge of -3. [Elsbach and Weiss (1981), supra.] A proteolyticN-terminal fragment of BPI having a molecular weight of about 25 kD hasan amphipathic character, containing alternating hydrophobic andhydrophilic regions. This N-termina fragment of human BPI possesses theanti-bacteria efficacy of the naturally-derived 55 kD human BPIholoprotein. [Ooi et at., J. Bio. Chem., 262:14891-14894 (1987)]. Incontrast to the N-terminal portion, the C-terminal region of theisolated human BPI protein displays only slightly detectableanti-bacterial activity against gram-negative organisms. [Ooi et at., J.Exp. Med., 174:649 (1991).] An N-terminal BPI fragment of approximately23 kD, referred to as "rBPI₂₃," has been produced by recombinant meansand also retains anti-bacterial activity against gram-negativeorganisms. Gazzano-Santoro et al., Infect. Immun. 60:4754-4761 (1992).

The bactericidal effect of BPI has been reported to be highly specificto gram-negative species, e.g., in Elsbach and Weiss, Inflammation:Basic Principles and Clinical Correlates, eds. Gallin et at., Chapter30, Raven Press, Ltd. (1992). BPI is commonly thought to be non-toxicfor other microorganisms, including yeast, and for higher eukaryoticcells. Elsbach and Weiss (1992), supra, reported that BPI exhibitsanti-bacterial activity towards a broad range of gram-negative bacteriaat concentrations as low as 10⁻⁸ to 10⁻⁹ M, but that 100- to 1,000-foldhigher concentrations of BPI were non-toxic to all of the gram-positivebacterial species, yeasts, and higher eukaryotic cells tested at thattime. It was also reported that BPI at a concentration of 10-6M or 160μg/ml had no toxic effect, when tested at a pH of either 7.0 or 5.5, onthe gram-positive organisms Staphylococcus aureus (four strains),Staphylococcus epidermidis, Streptococcus faecalis, Bacillus subtills,Micrococcus lysodeikticus, and Listeria monocytogenes. BPI at 10⁻⁶ Mreportedly had no toxic effect on the fungi Candida albicans and Candidaparapsilosis at pH 7.0 or 5.5, and was non-toxic to higher eukaryoticcells such as human, robbit and sheep red blood cells and several humanrumor cell lines. See also Elsbach and Weiss, Advances in InflammationResearch, ed. G. Weissmann, Vol. 2, pages 95-113 Raven Press (1981 ).This reported target cell specificity was believed to be the result ofthe strong attraction of BPI for lipopolysaccharide (LPS), which isunique to the outer membrane (or envelope) of gram-negative organisms.

The precise mechanism by which BPI kills gram-negative bacteria is notyet completely elucidated, but it is believed that BPI must first bindto the surface of the bacteria through electrostatic and hydrophobicinteractions between the cationic BPI protein and negatively chargedsites on LPS. LPS has been referred to as "endotoxin" because of thepotent inflammatory response that it stimulates, i.e., the release ofmediators by host inflammatory cells which may ultimately result inirreversible endotoxic shock. BPI binds to lipid A, reported to be themost toxic and most biologically active component of LPS.

In susceptible gram-negative bacteria, BPI binding is thought to disruptLPS structure, leading to activation of bacterial enzymes that degradephospholipids and peptidoglycans, altering the permeability of thecell's outer membrane, and initiating events that ultimately lead tocell death. [Elsbach and Weiss (1992), supra]. BPI is thought to act intwo stages. The first is a sublethal stage that is characterized byimmediate growth arrest, permeabilization of the outer membrane andselective activation of bacterial enzymes that hydrolyze phospholipidsand peptidoglycans. Bacteria at this stage can be rescued by growth inserum albumin supplemented media [Mannion et al., J. Clin. Invest.,85:853-860 (1990)]. The second stage, deftned by growth inhibition thatcannot be reversed by serum albumin, occurs after prolonged exposure ofthe bacteria to BPI and is characterized by extensive physiologic andstructural changes, including apparent damage to the inner cytoplasmicmembrane.

Initial binding of BPI to LPS leads to organizational changes thatprobably result from binding to the anionic groups in the KDO region ofLPS, which normally stabilize the outer membrane through binding of Mg⁺⁺and Ca⁺⁺. Attachment of BPI to the outer membrane of gram-negativebacteria produces rapid permeabitization of the outer membrane tohydrophobic agents such as actinomycin D. Binding of BPI and subsequentgram-negative bacterial killing depends, at least in part, upon the LPSpolysacchafide chain length, with long O-chain bearing, "smooth"organisms being more resistant to BPI bactericidal effects than shortO-chain beating, "rough" organisms [Weiss et al., J. Clin. Invest.65:619-628 (1980)]. This first stage of BPI action, permeabilization ofthe gram-negative outer envelope, is reversible upon dissociation of theBPI, a process requiting the presence of divalent cations and synthesisof new LPS [Weiss et al., J. Immunol. 132:3109-3115 (1984)]. Loss ofgram-negative bacterial viability, however, is not reversed by processeswhich restore the envelope integrity. suggesting that the bactericidalaction is mediated by additional lesions induced in the target organismand which may be situated at the cytoplasmic membrane (Mannion et at.,J. Clin. Invest. 86:631-64 1 (1990)). Specific investigation of thispossibility has shown that on a molar basis BPI is at least asinhibitory of cytoplasmic membrane vesicle function as polymyxin B (In'tVeld et at., Infection and Immunity 56:1203-1208 (1988)) but the exactmechanism as well as the relevance of such vesicles to studies of intactorganisms has not yet been elucidated.

BPI is also capable of neutralizing the endotoxic properties of LPS towhich it binds. Because of its bactericidal properties for gram-negativeorganisms and its ability to neutralize LPS, BPI can be utilized for thetreatment of mammals suffering from diseases caused by gram-negativebacteria, such as bacteremia or sepsis.

U.S. Pat. No. 5,198,541 discloses recombinant genes encoding and methodsfor expression of BPI proteins, including BPI holoprotein and fragmentsof BPI. It also describes the use of N-terminal fragments of BPI proteinfor co-treatment with certain antibiotics, specifically penicillin,cephalosporins, rifampicin and actinomycin D.

Gram-negative bacteria include bacteria from the following species:Acidarninococcus, Acinetobacter, Aeromonas, Alcaligenes, Bacteroides,Bordetella, Branhamella, Brucella, Calymmatobacterium, Carnpylobacter,Cardiobacterium, Chromobacterium, Citrobacter, Edwardsiella,Enterobacter, Escherichia, Flavobacterium, Francisella, Fusobacterium,Haermophilus, Klebsiella, Legionella, Moraxella, Morganella, Neisseria,Pasturella, Plesiornonas, Proteus, Providencia, Pseudomonas, Salmonella,Serratia, Shigella, Streptobacillus, Veillonella, Vibrio, and Yersiniaspecies.

Antibiotics are natural chemical substances of relatively low molecularweight produced by various species of microorganisms, such as bacteria(including Bacillus species), actinomycetes (including Streptomyces) andfungi, that inhibit growth of or destroy other microorganisms.Substances of similar structure and mode of action may be synthesizedchemically, or natural compounds may be modified to producesemi-synthetic antibiotics. These biosynthetic and semi-syntheticderivatives are also effective as antibiotics. The major classes ofantibiotics are (1) the β-lactams, including the penicillins,cephalosporins and monobactams; (2) the aminoglycosides, e.g.,gentamicin, tobramycin, netilmycin, and amikacin; (3) the tetracyclines;(4) the sulfonamides and trimethoprim; (5) the fluoroquinolones, e.g.,ciprofloxacin, norfloxacin, and ofloxacin; (6) vancomycin; (7) themacrolides, which include for example, erythromycin, azithromycin, andclarithromycin; and (8) other antibiotics, e.g., the polymyxins,chloramphenicol and the lincosamides.

Antibiotics accomplish their anti-bacterial effect through severalmechanisms of action Which can be generally grouped as follows: (1)agents acting on the bacterial cell wall such as bacitracin, thecephalosporins, cycloserine, fosfomycin, the penicillins, ristocetin,and vancomycin; (2) agents affecting the cell membrane or exerting adetergent effect, such as colistin, novobiocin and polymyxins; (3)agents affecting cellular mechanisms of replication, informationtransfer, and protein synthesis by their effects on ribosomes, e.g., theaminoglycosides, the tetracyclines, chloramphenicol, clindamycin,cycloheximide, fucidin, lincomycin, puromycin, rifampicin, otherstreptomycins, and the macrolide antibiotics such as erythromycin andoleandomycin; (4) agents affecting nucleic acid metabolism, e.g., thefluoroquinolones, actinomycin, ethambutol, 5-fluorocytosine,griseofulvin, rifamycins; and (5) drugs affecting intermediarymetabolism, such as the sulfonamides, trimethoprim, and thetuberculostatic agents isoniazid and para-aminosalicylic acid. Someagents may have more than one primary mechanism of action, especially athigh concentrations. In addition, secondary changes in the structure ormetabolism of the bacterial cell often occur after the primary effect ofthe antimicrobial drug.

The penicillins have a characteristic double-ring system composed of aβ-lactam ring, which provides the antibacterial activity, and athiazolidene ring. The penicillins are differentiated by a single sidechain that is unique for each penicillin. The compounds are bactericidaland act by inhibiting bacterial transpeptidase, an enzyme involved insynthesis of the bacterial cell wall. Because of their mechanism ofaction, penicillins are generally active against growing, but notresting, cells. Penicillins, especially penicillin G, have largelygram-positive activity; the relative insensitivity of gram-negative rodsto penicillin G and several other penicillins is probably due to thepermeability barrier of the outer membrane of gram-negative bacteria.Ampicillin, carbenicillin, ticarcillin, and some other penicillins areactive against gram-negative bacteria because they can pass through thisouter membrane. Penicillins have relatively few adverse effects, themost important of which are the hypersensitivity (allergic) reactions.These compounds are widely distributed in the body, but do not entercells and do not usually accumulate in CSF.

Bacterial resistance to the penicillins is by production of the enzymeβ-lactamase, which catalyzes hydrolysis of the β-lactam ring. Thepercentage of bacteria resistant to penicillin has risen to about 80%.Several penicillins, including methicillin, oxacillin, cloxacillin,dicloxacillin and nafcillin, are not affected by the β-lactamase ofstaphylococci. These antibiotics are useful against mostβ-lactamase-producing species of Staphylococcus. However, a small numberof species are resistant even to these penicillins. Some penicillins,amoxicillin and ticarcillin, are marketed in combination with clavulanicacid, which is a β-lactamase inhibitor that covalently binds to theenzyme and prevents it from hydrolyzing the antibiotics. Anotherinhibitor, sulbactam, is marketed in combination with ampicillin.

The cephalosporins are characterized by a β-lactam ring, like thepenicillins, but have an adjacent dihydrothiazine ring instead of athiazolidene ring. For convenience, these compounds are generallyclassified by generations. The first generation includes cephalothin,cephapirin, cefazolin, cephalexin, cephradine and cefadroxil. Thesedrugs generally have excellent gram-positive activity except forenterococci and methicillin-resistant staphylococci, and have onlymodest gram-negative coverage. The second generation includescefamandole, cefoxitin, ceforanide, cefuroxime, cefuroxime axetil,cefaclor, cefonicid and cefotetan. This generation generally loses somegram-positive activity by weight and gains limited gram-negativecoverage. The third generation includes cefotaxime, moxalactam,ceftizoxime, ceftriaxone, cefoperazone and ceftazidime. These compoundsgenerally sacrifice further gram-positive activity by weight but gainsubstantial gram-negative coverage against Enterobacter and sometimesare active against Pseudornonas. The cephalosporins bind topenicillin-binding proteins with varying affinity. Once binding occurs,protein synthesis is inhibited. Cephalosporins are usually welltolerated; adverse effects include hypersensitivity reactions andgastrointestinal effects. Cephalosporins may interact with nephrotoxicdrags. particularly aminoglycosides. to increase toxicity. Resistance tocephalosporins is mediated by several mechanisms, including productionof β-lactamase, although some strains that do not produce β-lactamaseare nevertheless resistant.

Imipenem is a N-formimidoyl derivative of the mold product thienamycin.It contains a β-lactam ring and somewhat resembles penicillin except fordifferences in the second ring. It has activity against bothgram-positive and gram-negative organisms and is resistant to mostβ-lactamases, although not those from Pseudomonas. It is marketed incombination with cilastin, a compound that inhibits inactivation ofimipenem in the kidney by renal dihydropeptidase I enzyme. Cilastinincreases the concentration of imipenem in urine, although not in blood.

Aztreonam is the first of a new group of antibiotics referred to as themonobactams. These agents have a β-lactam ring but lack the second ringcharacteristic of the penicillins and cephalosporins. It acts by bindingto penicillin-binding proteins, and produces long, filamentous bacterialshapes that eventually lyse. Aztreonam is active only against aerobicgram-negative bacteria, is susceptible to inactivation by someβ-lactamases, and has few adverse effects.

The aminoglycosides contain amino sugars linked to an aminocyclitol ringby glycosidic bonds. They have similar mechanisms of action andproperties, but differ somewhat in spectrum of action, toxicity, andsusceptibility to bacterial resistance. The compounds are bactericidal,with activity against both gram-positive and gram-negative organisms,and act by binding to proteins on the 30S ribosome of bacteria andinhibiting protein synthesis. The aminoglycosides also bind to isolatedLPS and have a very weak outer membrane permeabilizing effect. [Taber etal., Microbiological Reviews 53:439-457 (1987)); Kadurugamuwa et al.,Antimicrobial Agents and Chemotherapy, 37:715-721 (1993); Vaara,Microbiological Reviews 56: 395-411 (1992)]. This class of antibioticsincludes amikacin, gentamicin, kanamycin, neomycin, netilmycin,paromomycin and tobramycin. The aminoglycosides are usually reserved formore serious infections because of severe adverse effects includingototoxicity and nephrotoxicity. There is a narrow therapeutic windowbetween the concentration required to produce a therapeutic effect,e.g., 8 μg/ml for gentamicin, and the concentration that produces atoxic effect, e.g., 12 μg/ml for gentamicin. Neomycin in particular ishighly toxic and is never administered parenterally.

Tetracyclines have a common four-ring structure and are closelycongeneric derivatives of the polycyclic naphthacenecarboxamide. Thecompounds are bacteriostatic, and inhibit protein synthesis by bindingto the 30S subunit of microbial ribosomes and interfering withattachment of aminoacyl tRNA. The compounds have some activity againstboth gram-positive and gram-negative bacteria; however, their use islimited because many species are now relatively resistant. Adverseeffects include gastrointestinal effects, hepatotoxicity with largedoses, and nephrotoxicity in some patients. This antibiotic classincludes tetracycline, chlortetracycline, demeclocycline, doxycycline,methacycline, minocycline and oxytetracycline.

The sulfonamides are derivatives of sulfanilamide, a compound similar instructure to para-aminobenzoic acid (PABA), which is an essentialprecursor for bacterial synthesis of folic acid. The compounds aregenerally bactefiostatic, and act by competitively inhibitingincorporation of PABA into tetrahydrofolic acid, which is a requiredcofactor in the synthesis of thymidines, purines and DNA. Sulfonamideshave a wide range of activity against gram-positive and gram-negativebacteria, but their usefulness has diminished with increasingly highprevalence of bacterial resistance. The sulfonamide class of antibioticsincludes sulfacytine, sulfadiazine, sulfamethizole, sulfisoxazole,sulfamethoxazole, sulfabenzamide and sulfacetamide. Adverse effectsinclude hypersensitivity reactions and occasional hematologicaltoxicity.

Trimethoprim is an inhibitor of the dihydrofolate reductase enzyme,which converts dihydrofolic to tetrahydrofolic acid, a required factorfor DNA synthesis. Adverse effects include gastrointestinal distress andrare hematological toxicity. Trimethoprim is also available incombination with sulfamethoxazole (also known as co-trimoxazole). Thecombination is usually bactericidal, although each agent singly isusually bacteriostatic. The combination is the drug of choice forSalmonella infections, some Shigella infections, E. coli traveler'sdiarrhea and Pneumocysas carinii pneumonia.

The fluoroquinolones and quinolones are derivatives of nalidixic acid, anaphthyridine derivative. These compounds are bactericidal, and impairDNA replication, transcription and repair by binding to the DNA andinterfering with DNA gyrase, an enzyme which catalyzes negativesupercoiling of DNA. The fluoroquinolones, which include norfloxacin,ciprofioxacin, and ofloxacin, and the quinolones, which includecinoxacin, have a broad spectrum of antimicrobial activity againstgram-negative and gram-positive organisms. These compounds distributewidely through extravascular tissue sites, have a long serum half-life,and present few adverse effects. Because of their effect on DNA, thedrugs are contraindicated in pregnant patients and in children whoseskeletal growth is incomplete.

Vancomycin is a glycopeptide, with a molecular weight of about 1500,produced by a fungus. It is primarily active against gram-positivebacteria. The drug inhibits one of the final steps in synthesis of thebacterial cell wall, and is thus effective only against growingorganisms. It is used to treat serious infections due to gram-positivecocci when penicillin G is not useful because of bacterial resistance orpatient allergies. Vancomycin has two major adverse effects, ototoxicityand nephrotoxicity. These toxicities can be potentiated by concurrentadministration of another drug with the same adverse effect, such as anaminoglycoside.

The macrolides are bacteriostatic and act by binding to the 50S subunitof 70S ribosomes, resulting in inhibition of protein synthesis. Theyhave a broad spectrum of activity against gram-positive andgram-negative bacteria and may be bacteriostatic or bactericidal,depending on the concentration achieved at sites of infection. Thecompounds distribute widely in body fluids. Adverse effects includegastrointestinal distress and rare hypersensitivity reactions. The mostcommon macrofide used is erythromycin, but the class includes othercompounds such as clarithromycin and azithromycin.

The polymyxins are a group of closely related antibiotic substancesproduced by strains of Bacillus polymyxa. These drugs, which arecationic detergents, are relatively simple, basic peptides withmolecular weights of about 1000. Their antimicrobial activity isrestricted to gram-negative bacteria. They interact strongly withphospholipids and act by penetrating into and disrupting the structureof cell membranes. Polymyxin B also binds to the lipid A portion ofendotoxin and neutralizes the toxic effects of this molecule. PolymyxinB has severe adverse effects, including nephrotoxicity andneurotoxicity, and should not be administered concurrently with othernephrotoxic or neurotoxic drugs. The drug thus has limited use as atherapeutic agent because of high systemic toxicity, but may be used forsevere infections, such as Pseudomonas aeruginosa meningitis, thatrespond poorly to other antibiotics.

Chloramphenicol inhibits protein synthesis by binding to the 50Sribosomal subunit and preventing binding of aminoacyl tRNA. It has afairly wide spectrum of antimicrobial activity, but is only reserved forserious infections, such as meningitis, typhus, typhoid fever, and RockyMountain spotted fever, because of its severe and fatal adversehematological effects. It is primarily bacteriostatic, although it maybe bactericidal to certain species.

Lincomycin and clindamycin are lincosamide antimicrobials. They consistof an amino acid linked to an amino sugar. Both inhibit proteinsynthesis by binding to the 50S ribosomal subunit. They compete witherythromycin and chloramphenicol for the same binding site but in anoverlapping fashion. They may be bacteriostatic or bactericidal,depending on relative concentration and susceptibility. Gastrointestinaldistress is the most common side effect. Other adverse reactions includecutaneous hypersensitivity, transient hematological abnormalities, andminor elevations of hepatic enzymes. Clindamycin is often the drug ofchoice for infections caused by anaerobic bacteria or mixedaerobic/anaerobic infections, and can also be used for susceptibleaerobic gram-positive cocci.

Some drugs, e.g. aminoglycosides, have a small therapeutic window. Forexample, 2 to 4 μg/ml of gentamicin or tobramycin may be required forinhibition of bacterial growth, but peak concentrations in plasma above6 to 10 μg/ml may result in ototoxicity or nephrotoxicity. These agentsare more difficult to administer because the ratio of toxic totherapeutic concentrations is very low. Antimicrobial agents that havetoxic effects on the kidneys and that are also eliminated primarily bythe kidneys, such as the aminoglycosides or vancomycin, requireparticular caution because reduced elimination can lead to increasedplasma concentrations. which in turn may cause increased toxicity. Dosesof antimicrobial agents that are eliminated by the kidneys must bereduced in patients with impaired renal function. Similarly, dosages ofdrugs that are metabolized or excreted by the liver, such aserythromycin, chloramphenicol, or clindamycin, must be reduced inpatients with decreased hepatic function.

Antibiotic resistance in bacteria is an increasingly troublesomeproblem. The accelerating development of antibiotic-resistant bacteria,intensified by the widespread use of antibiotics in farm animals andoverprescription of antibiotics by physicians, has been accompanied bydeclining research into new antibiotics with different modes of action.[Science, 264:360-374 (1994).] Antibiotic resistance, once acquired, canbe rapidly spread to other bacteria, including bacteria of a differentspecies. There are some species of bacteria that are resistant to allbut one antibiotic; it may be only a matter of time before theappearance of bacterial strains that are resistant to all antibiotics.

Bacteria acquire resistance to antibiotics through several mechanisms:(1) production of enzymes that destroy or inactivate the antibiotic[Davies, Science, 264:375-381 (1994)]; (2) synthesis of new or alteredtarget sites on or within the cell that axe not recognized by theantibiotic [Spratt, Science, 264:388-393 (1994)]; (3) low permeabilityto antibiotics, which can be reduced even further by altering cell wallproteins, thus restricting access of antibiotics to the bacterialcytoplasmic machinery; (4) reduced intracellular transport of the drug;and (5) increased removal of antibiotics from the cell viamembrane-associated pumps [Nikaido, Science, 264:382-387 (1994)].

The susceptibility of a bacterial species to an antibiotic is generallydetermined by two microbiological methods. A rapid but crude procedureuses commercially available filter paper disks that have beenimpregnated with a specific quantity of the antibiotic drug. These disksare placed on the surface of agar plates that have been streaked with aculture of the organism being tested, and the plates are observed forzones of growth inhibition. A more accurate technique, the brothdilution susceptibility test, involves preparing test tubes containingserial dilutions of the drug in liquid culture media, then inoculatingthe organism being tested into the tubes. The lowest concentration ofdrug that inhibits growth of the bacteria after a suitable period ofincubation is reported as the minimum inhibitory concentration.

The resistance or susceptibility of an organism to an antibiotic isdetermined on the basis of clinical outcome, i.e., whetheradministration of that antibiotic to a subject infected by that organismwill successfully cure the subject. While an organism may literally besusceptible to a high concentration of an antibiotic in vitro, theorganism may in fact be resistant to that antibiotic at physiologicallyrealistic concentrations. If the concentration of drug required toinhibit growth of or kill the organism is greater than the concentrationthat can safely be achieved without toxicity to the subject, themicroorganism is considered to be resistant to the antibiotic. Tofacilitate the identification of antibiotic resistance or susceptibilityusing in vitro test results, the National Committee for ClinicalLaboratory Standards (NCCLS) has formulated standards for antibioticsusceptibility that correlate clinical outcome to in vitrodeterminations of the minimum inhibitory concentration of antibiotic.

Thus, there exists a desire in the an for agents that could act asadjuncts to conventional antibiotic therapy and that could act toimprove the therapeutic effectiveness of antibiotics.

SUMMARY OF THE INVENTION

The present invention generally provides methods and compositions forprophylaxis or treatment of gram-negative bacterial infections, usingBPI protein products. The methods and compositions, in addition to beinguseful for treatment, are useful for prophylaxis of patients at highrisk of gram-negative bacterial infection, e.g., patients who willundergo abdominal or genitourinary surgery, or trauma victims.Specifically, the present invention provides, in a method for treating agram-negative bacterial infection with an antibiotic, the improvementcomprising the step of concurrently administering BPI protein product inan amount effective to improve the therapeutic effectiveness of theantibiotic.

The present invention is based upon the finding that BPI protein productis useful as adjunct therapy with conventional antibiotics, andspecifically the finding that concurrent administration, orco-treatment, of a BPI protein product and an antibiotic or combinationof antibiotics can improve the therapeutic effectiveness of theantibiotic or combination of antibiotics. BPI protein product mayimprove the therapeutic effectiveness of antibiotics in a variety ofways, including by increasing susceptibility of gram-negative bacteriato a reduced dosage of antibiotics, by effectively reversing resistanceof gram-negative bacteria to antibiotics, by providing synergistic orpotentiating effects beyond the individual or additive effects of theBPI protein product or antibiotic alone, or by neutralizing endotoxinreleased by bacteria killed by antibiotics. Concurrent administration ofBPI protein product and antibiotic provides unexpectedly superiortherapeutic effects in vivo than either agent provides when administeredalone. Concurrent administration of BPI protein product according tothis improved method of treatment is effective even when thegram-negative bacteria involved are considered to be resistant to thebactericidal effects of BPI protein product alone and/or antibioticalone.

The present invention provides a use of a BPI protein product for themanufacture of a medicament for the co-treatment with an antibiotic of agram-negative bacterial infection in mammals. This aspect of theinvention contemplates co-treatment with any antibiotic or combinationsof antibiotics, including β-lactam antibiotics with and withoutβ-lactamase inhibitors, aminoglycosides, tetracyclines, suffonamides andtrimethoprim, vancomycin, macrofides, fluoroquinolones and quinolones,polymyxins and other antibiotics.

This aspect of the invention also provides the use of a BPI proteinproduct for the manufacture of a medicament for improving thetherapeutic effectiveness of antibiotics in a gram-negative bacterialinfection, use of a BPI protein product for the manufacture of amedicament for increasing the susceptibility to an antibiotic ofgram-negative bacteria involved in the gram-negative bacterialinfection, and use of a BPI protein product for the manufacture of amedicament for reversing resistance to an antibiotic of gram-negativebacteria involved in the gram-negative bacterial infection.

The invention utilizes any of the large variety of BPI protein productsknown to the art including natural BPI protein, recombinant BPI protein,BPI fragments, BPI analogs, BPI variants, and BPI peptides. Concurrentadministration of BPI protein product with any antibiotic or combinationof antibiotics is contemplated, including β-lactam antibiotics with orwithout β-lactamase inhibitors, aminoglycosides, tetracyclines,sulfonamides and trimethoprim, vancomycin, macrolides, fluoroquinolonesand quinolones, polymyxins, and other antibiotics.

Either the BPI protein product or the antibiotic may be administeredsystemically or topically to a subject suffering from a suspected orconfirmed gramnegative bacterial infection. The BPI protein product andantibiotic may be administered by different routes and may beadministered simultaneously or sequentially.

The invention also provides pharmaceutical compositions for treatment ofgram-negative bacterial infections, comprising an antibiotic and a BPIprotein product in an amount effective to improve the therapeuticeffectiveness of the antibiotic. Such compositions optionally comprisepharmaceutically acceptable diluents, adjuvants or carriers. Thecompositions may be formulated for systemic or topical administration tosubjects. In addition, compositions comprising BPI protein product andan antibiotic can be used in a variety of in vitro uses, such as use asa bactericide to decontaminate fluids and surfaces and to sterilizesurgical and other medical equipment and implantable devices, includingprosthetic joints.

Numerous additional aspects and advantages of the invention will becomeapparent to those skilled in the art upon consideration of the followingdetailed description of the invention which describes presentlypreferred embodiments thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts survival data after treatment with rBPI₂₁ andcefamandole, separately or in combination, in an E. coli O 111:B4 mouseperitonitis assay.

FIGS. 2-4 relate to results from an E. coli O111:B4 mouse peritonitisassay with rBPI₂₁ and cefamandole, separately or in combination. FIG. 2depicts survival data; FIG. 3 shows bacterial counts from peritoneallavage fluid; and FIG. 4 shows bacterial counts in blood.

FIGS. 5A and 5B display results from two trials of treatment with rBPI₂₁and cefamandole, separately or in combination, in an E. coli O7:K1 mouseperitonitis assay.

FIGS. 6-16 relate to results, including cardiovascular and metabolicfindings, from an E. coli O7:K1 rabbit bacteremia assay with rBPI₂₁ andcefamandole, separately or in combination. FIG. 6 depicts survival data;FIG. 7 shows bacterial count in blood, which FIG. 8 displays aspercentage of bacterial dose; FIG. 9 shows blood endotoxin levels; FIGS.10 shows mean arterial blood pressure; FIG. 11, cardiac index; FIG. 12,total peripheral resistance; FIG. 13, arterial oxygen tension; FIG. 14,alveolar-artefial oxygen gradient; FIG. 15, respiration rate; and FIG.16, arterial blood pH.

FIG. 17 depicts survival data after treatment with rBPI₂₁ andgentamicin, separately or in combination, in an E. coli O7:K1 mouseperitonitis assay.

FIG. 18 shows the bactericidal effect of rBPI₂₁ and cefifiaxone,separately or in combination, on growth of ceftfiaxone-resistant E.coli.

FIGS. 19-25 relate to the synergistic effect of rBPI₂₁ on antibiotickilling curves for selected gram-negative organisms. FIG. 19 shows thebactericidal effect of rBPI₂₁ alone. FIG. 20 shows the effect of rBPI₂₁in combination with trimethoprim/suffamethoxazole; FIG. 21, rBPI₂₁ withciprofloxacin; FIG. 22, rBPI₂₁ with piperacillin; FIG. 23, rBPI₂₁ withcefotaxime; FIG. 24, rBPI₂₁ with cefuroxime; and FIG. 25, rBPI₂₁ withamikacin.

DETAILED DESCRIPTION

The present invention relates to methods and compositions for treating agram-negative bacterial infection, using a BPI protein product. Theinvention is based on the unexpected discovery that, when treating agram-negative bacterial infection with an antibiotic, the concurrentadministration of BPI protein product with the antibiotic improves thetherapeutic effectiveness of the antibiotic, even at doses at which theBPI protein product alone or antibiotic alone may be inactive. BPIprotein product by itself typically has an antibacterial potency lessthan that of conventional antibiotics. However, because itsadministration unexpectedly improves the therapeutic effectiveness ofconventional antibiotic therapy. BPI protein product is useful asadjunct therapy with conventional antibiotic therapy for the treatmentof gram-negative bacterial infections.

"Gram-negative bacterial infection," as used herein, encompassesconditions associated with or resulting from gram-negative bacterialinfection (e.g., sequelae). These conditions include gram-negativesepsis, endotoxin-related hypotension and shock, and one or more of theconditions associated therewith, including fever, metabolic acidosis,disseminated intravascular coagulation and related clotting disorders,anemia, thrombocytopenia, leukopenia, adult respiratory distresssyndrome and related pulmonary disorders, renal failure and relatedrenal disorders, hepatobiliary disease and central nervous systemdisorders. These conditions also include translocation of bacteria fromthe intestines and concomitant release of endotoxin.

BPI protein product may improve the therapeutic effectiveness of theantibiotic in a variety of ways, including by increasing susceptibilityof gram-negative bacteria to a reduced dosage of antibiotics, byeffectively reversing resistance of gram-negative bacteria toantibiotics, by providing synergistic or potentiating effects beyond theindividual or additive effects of the BPI protein product or antibioticalone, or by neutralizing endotoxin released by bacteria killed byantibiotics. Concurrent administration of BPI protein product andantibiotic is expected to provide more effective treatment ofgram-negative bacterial infection. Concurrent administration of the twoagents may provide greater therapeutic effects in vivo than either agentprovides when administered singly. It may permit a reduction in thedosage of one or both agents with achievement of a similar therapeuticeffect. Alternatively, the concurrent administration may produce a morerapid or complete bactericidal/bacteriostatic effect than could beachieved with either agent alone.

Therapeutic effectiveness is based on a successful clinical outcome, anddoes not require that the antimicrobial agent or agents kill 100% of theorganisms involved in the infection. Success depends on achieving alevel of antibacterial activity at the site of infection that issufficient to inhibit the bacteria in a manner that tips the balance infavor of the host. When host defenses are maximally effective, theantibacterial effect required may be minimal. Reducing organism load byeven one log (a factor of 10) may permit the host's own defenses tocontrol the infection. In addition, augmenting an earlybactericidal/baeteriostatic effect can be more important than long-termbactericidal/bacteriostatic effect. These early events are a significantand critical part of therapeutic success, because they allow time forhost defense mechanisms to activate. Increasing the bactericidal ratemay be particularly important for infections such as meningitis, bone orjoint infections. [Stratton, Antibiotics in Laboratory Medicine, 3rd ed.(Lorian, V., Ed.) pp. 849-879, Williams and Wilkins, Baltimore Md.(1991)].

The effect of BPI protein product to improve the therapeuticeffectiveness of antibiotics in vivo may be demonstrated in in vivoanimal models, or may be predicted on the basis of a variety of in vitrotests, including (1) determinations of the minimum inhibitoryconcentration (MIC) of an antibiotic required to inhibit growth of agram-negative organism for 24 hours, (2) determinations of the effect ofan antibiotic on the kinetic growth curve of a gram-negative organism,and (3) checkerboard assays of the MIC of serial dilutions of antibioticalone or in combination with serial dilutions of BPI protein product.Exemplary models or tests are described in Eliopoulos and Moellering InAntibiotics in Laboratory Medicine, 3rd ed. (Lorian, V., Ed.) pp.432-492, Williams and Wilkins, Baltimore Md. (1991 ).

Using in vitro determinations of antibiotic MIC at 24 hours, a BPIprotein product may be shown to reduce the MIC of the antibiotic. Withthis result, it is expected that concurrent administration of the BPIprotein product in vivo will increase susceptibility of thegram-negative organism to the antibiotic. A BPI protein product may alsobe shown to reduce the MIC of an antibiotic from the range in which theorganism is considered clinically resistant to a range in which theorganism is considered clinically susceptible. With this result, it isexpected that concurrent administration in vivo of the BPI proteinproduct with the antibiotic will reverse resistance and effectivelyconvert the antibiotic-resistant organism into an antibiotic-susceptibleorganism.

By measuring the effect of antibiotics on the in vitro growth curves ofgram-negative organisms, in the presence or absence of a BPI proteinproduct, the BPI protein product may be shown to enhance the earlyantibacterial effect of antibiotics at 0-24 hours. Enhancement of earlybactericidal/growth inhibitory effects is important in determiningtherapeutic outcome.

The BPI protein product and antibiotic may also be shown to havesynergistic or potentiating effects beyond the individual effects ofeach agent alone or the additive effects of the agents together. In acheckerboard assay, the combination of BPI protein product withantibiotics may be shown to result in a "synergistic" fractionalinhibitory concentration index (FIC). The checkerboard method is basedon additivity, which assumes that the result observed with multipledrugs is the sum of the separate effects of the drugs being tested;according to this system a FIC of less than 0.5 is scored as synergy, 1is scored as additive, and greater than 1 but less than 2 is scored asindifferent. In contrast, kinetic assays are based on the idea that onlyone metabolic pathway at a time can be growth rate-limiting for anorganism; according to this system, the combined effect of drugs that donot interact with one another (autonomous or indifferent) is simply theeffect of the most active drug alone.

Concurrent administration of BPI protein products and antibiotics isshown herein to lower MICs of a variety of antibiotics for a variety ofgram-negative organisms. It is also shown to reverse resistance of avariety of gmrn-negative organisms to antibiotics. In some cases whereBPI protein product does not affect the MIC of antibiotic at 24 hours,BPI protein product is shown herein to enhance the early bactericidaleffect of antibiotics on growth curves at 0-7 or 7-24 hours. The BPIprotein products exert these effects even on gram-negative organismsthat are not considered susceptible to the direct bactericidal or growthinhibitory effects of BPI protein product alone. It is also shown hereinthat the concurrent administration of BPI protein products withantibiotics in vivo allows a reduction in the dosages of both agents toamounts that, if administered alone, would be insufficient to exert thesame clinical effect.

Either the BPI protein product or the antibiotic, or both, may beadministered at levels at which neither would alone be therapeuticallyeffective against a gram-negative bacterial infection. Alternatively,according to a preferred method, the antibiotic and BPI protein productcan be administered in amounts where each would alone be therapeuticallyeffective against a gram-negative bacterial infection but wherein thecombination of the two antibiotics provides even more potent effects.The BPI protein product may be administered in an amount which increasessusceptibility of gram-negative bacteria to reduced antibiotic dosage,or in an amount which reverses resistance of the gram-negative bacteriato an antibiotic.

BPI protein product is thought to interact with a variety of hostdefense elements present in whole blood or serum, including complement,p15 and LBP, and other cells and components of the immune system. Suchinteractions may result in potentiation of the activities of BPI proteinproduct. Because of these interactions, BPI protein products can beexpected to exert even greater activity in vivo than in vitro. Thus,while in vitro tests are predictive of in vivo utility, absence ofactivity in vitro does not necessarily indicate absence of activity invivo. For example, BPI has been observed to display a greaterbactericidal effect on gram-negative bacteria in whole blood or plasmaassays than in assays using conventional media. [Weiss et al., J. Clin.Invest. 90:1122-1130 (1992)]. This may be because conventional in vitrosystems lack the blood elements that facilitate or potentiate BPI'sfunction in vivo, or because conventional media contain higher thanphysiological concentrations of magnesium and calcium, which aretypically inhibitors of the antibacterial activity of BPI proteinproducts. Furthermore, in the host, BPI protein product is available toneutralize endotoxin released during antibiotic killing of bacteria, afurther clinical benefit not seen in or predicted by in vitro tests.

It is also contemplated that the BPI protein product be administeredwith other products that potentiate the bactericidal activity of BPIprotein products. For example, serum complement potentiates thegram-negative bactericidal activity of BPI protein products; thecombination of BPI protein product and serum complement providessynergistic bactericidal/growth inhibitory effects. See, e.g., Ooi etal. J. Biol. Chem., 265:15956 (1990) and Levy et al. J. Biol. Chem.,268: 6038-6083 (1993) which address naturally-occurring 15 kD proteinspotentiating BPI antibacterial activity. See also co-owned, co-pendingPCT Application No. US94/07834 filed Jul. 13, 1994, which corresponds toU.S. patent application Ser. No. 08/274,303 filed Jul. 11, 1994 as acontinuation-in-part of U.S. patent application Ser. No. 08/093,201, nowabandoned, filed Jul. 14, 1993. These applications, which are allincorporated herein by reference, describe methods for potenfiatinggram-negative bactericidal activity of BPI protein products byadministering lipopolysaccharide binding protein (LBP) and LBP proteinproducts. LBP protein derivatives and derivative hybrids which lackCD-14 immunostimulatory properties are described in PCT Application No.US94/06931 filed Jun. 17, 1994, which corresponds to co-owned,co-pending U.S. patent application Ser. No. 08/261,660, filed Jun. 17,1994 as a continuation-in-part of U.S. patent application Ser. No.08/079,510, now abandoned, filed Jun. 17, 1993, the disclosures of allof which are hereby incorporated by reference.

An advantage provided by the present invention is the ability to providemore effective treatment of gram-negative bacterial infection by virtueof the improved therapeutic effectiveness of the antibiotic treatment.Another advantage is the ability to treat gram-negative organisms thatare normally resistant to one or more antibiotics. Yet another advantageis the ability to accelerate the killing of gram-negative organisms byantibiotics. An additional advantage is the ability to neutralizeendotoxin released during antibiotic killing of bacteria. A furtheradvantage is the ability to use lower concentrations of toxicantibiotics such as gentamicin and polymyxin B, or expensive antibioticssuch as vancomycin. Because the use of some antibiotics is limited bytheir systemic toxicity or prohibitive cost, lowering the concentrationof antibiotic required for therapeutic effectiveness reduces toxicityand/or cost of treatment, and thus allows wider use of the antibiotic.The present invention may also provide quality of life benefits due to,e.g., decreased duration of therapy, reduced stay in intensive careunits or overall in the hospital, with the concomitant reduced risk ofserious nosocomial (hospital-acquired) infections.

The invention further provides pharmaceutical compositions for treatmentof gram-negative bacterial infections, comprising an antibiotic and aBPI protein product in an amount effective to improve the therapeuticeffectiveness of the antibiotic. Such compositions optionally comprisepharmaceutically acceptable diluents, adjuvants or carriers. Thecompositions may be formulated for systemic or topical administration tosubjects. In addition. antiseptic compositions comprising BPI proteinproduct and an antibiotic can be used in a variety of in vitro uses suchas use as a bacteficide to alecontaminate fluids and surfaces and tosterilize surgical and other medical equipment and implantable devices,including prosthetic joints. The invention also provides improvedmethods of in vitro decontamination of fluids and surfaces comprisingadministering a BPI protein product in combination with an antibiotic.

Either the BPI protein product or the antibiotics may be administeredsystemically or topically. Systemic routes of administration includeoral, intravenous, intramuscular or subcutaneous injection, intrathecal,intraperitoneal (e.g. by intraperitoneal lavage), transpulmonary usingaerosolized or nebulized drug, or transdermal. Topical routes includeadministration in the form of salves, ophthalmic drops, ear drops, orirrigation fluids (for, e.g., irrigation of wounds).

"Concurrent administration," or co-treatment, as used herein includesadministration of the agents together, or before or after each other.The BPI protein product and antibiotics may be administered by differentroutes. For example, the BPI protein product may be administeredintravenously while the antibiotics are administered intramuscularly,intravenously, subcutaneously, orally or intraperitoneally.Alternatively, the BPI protein product may be administeredintraperitoneally while the antibiotics are administeredintraperitoneally or intravenously, or the BPI protein product may beadministered in an aerosolized or nebulized form while the antibioticsare administered, e.g., intravenously. The BPI protein product andantibiotics are preferably both administered intravenously. The BPIprotein product and antibiotics may be given sequentially in the sameintravenous line, after an intermediate flush, or may be given indifferent intravenous lines. The BPI protein product and antibiotics maybe administered simultaneously or sequentially, as long as they aregiven in a manner sufficient to allow both agents to achieve effectiveconcentrations at the site of infection.

As used herein, "BPI protein product" includes naturally andrecombinantly produced BPI protein; natural, synthetic, and recombinantbiologically active polypeptide fragments of BPI protein; biologicallyactive polypeptide variants of BPI protein or fragments thereof,including hybrid fusion proteins and dimers; and biologically activepolypeptide analogs of BPI protein or fragments or variants thereof,including cysteine-substituted analogs. The BPI protein productsadministered according to this invention may be generated and/orisolated by any means known in the art. U.S. Pat. No. 5,198,541, thedisclosure of which is incorporated herein by reference, disclosesrecombinant genes encoding and methods for expression of BPI proteinsincluding recombinant BPI holoprotein, referred to as rBPI₅₀ andrecombinant fragments of BPI. Co-owned, copending U.S. patentapplication Ser. No. 07/885,501, now abandoned, and acontinuation-in-part thereof, U.S. patent application Ser. No.08/072,063, now U.S. Pat. No. 5,439,807, filed May 19, 1993 andcorresponding PCT Application No. 93/04752 filed May 19, 1993, which areall incorporated herein by reference, disclose novel methods for thepurification of recombinant BPI protein products expressed in andsecreted from genetically transformed mammalian host cells in cultureand discloses how one may produce large quantities of recombinant BPIproducts suitable for incorporation into stable, homogeneouspharmaceutical preparations.

Biologically active fragments of BPI (BPI fragments) includebiologically active molecules that have the same or similar amino acidsequence as a natural human BPI holoprotein, except that the fragmentmolecule lacks amino-terminal amino acids, internal amino acids, and/orcaxboxy-terminal amino acids of the holoprotein. Nonlimiting examples ofsuch fragments include a N-terminal fragment of natural human BPI ofapproximately 25 kD, described in Ooi et al., J. Exp. Med., 174:649(1991), and the recombinant expression product of DNA encodingN-terminal amino acids from 1 to about 193 or 199 of natural human BPI,described in Gazzano-Santoro et al., Infect. Immun. 60:4754-4761 (1992),and referred to as rBPI₂₃. In that publication, an expression vector wasused as a source of DNA encoding a recombinant expression product(rBPI₂₃) having the 31-residue signal sequence and the first 199 aminoacids of the N-terminus of the mature human BPI, as set out in FIG. 1 ofGray et al., supra, except that valine at position 151 is specified byGTG rather than GTC and residue 185 is glutamic acid (specified by GAG)rather than lysine (specified by AAG). Recombinant holoprotein (rBPI)has also been produced having the sequence (SEQ ID NOS: 145 and 146) setout in FIG. 1 of Gray et al., supra, with the exceptions noted forrBPI₂₃ and with the exception that residue 417 is alaninc (specified byGCT) rather than valine (specified by GTT). Other examples includedimeric forms of BPI fragments, as described in co-owned and co-pendingU.S. patent application Ser. No. 08/212,132, now U.S. Pat. No.5,447,913, filed Mar. 11, 1994, and corresponding PCT Application No.PCT/US95/03125 filed Mar. 13, 1995, the disclosures of which areincorporated herein by reference. Preferred dimeric products includedimeric BPI protein products wherein the monomers are amino-terminal BPIfragments having the N-terminal residues from about 1 to 175 to about 1to 199 of BPI holoprotein. A particularly preferred dimeric product isthe dimeric form of the BPI fragment having N-terminal residues 1through 193, designated rBPI₄₂ dimer.

Biologically active variants of BPI (BPI variants) include but are notlimited to recombinant hybrid fusion proteins, comprising BPIholoprotein or biologically active fragment thereof and at least aportion of at least one other polypeptide, and dimeric forms of BPIvariants. Examples of such hybrid fusion proteins and dimeric forms aredescribed by Theofan et al. in co-owned, copending U.S. patentapplication Ser. No. 07/885,911, now abandoned, and acontinuation-in-part application thereof, U.S. patent application Ser.No. 08/064,693 filed May 19, 1993 and corresponding PCT Application No.US93/04754 filed May 19, 1993, which are all incorporated herein byreference and include hybrid fusion proteins comprising, at theamino-terminal end, a BPI protein or a biologically active fragmentthereof and, at the carboxy-terminal end, at least one constant domainof an immunoglobulin heavy chain or allelic variant thereof.

Biologically active analogs of BPI (BPI analogs) include but are notlimited to BPI protein products wherein one or more amino acid residueshave been replaced by a different amino acid. For example, co-owned,copending U.S. patent application Ser. No. 08/013,801 filed Feb. 2,1993, now U.S. Pat. No. 5,420,019, and corresponding PCT Application No.US94/01235 filed Feb. 2, 1994, the disclosures of which are incorporatedherein by reference, discloses polypeptide analogs of BPI and BPIfragments wherein a cysteine residue is replaced by a different aminoacid. A preferred BPI protein product described by this application isthe expression product of DNA encoding from amino acid 1 toapproximately 193 or 199 of the N-terminal amino acids of BPIholoprotein, but wherein the cysteine at residue number 132 issubstituted with alanine and is designated rBPI₂₁ Δcys or rBPI₂₁. Otherexamples include dimeric forms of BPI analogs; e.g. co-owned andco-pending U.S. patent application Ser. No. 08/212,132, now U.S. Pat.No. 5,497,913, filed Mar. 11, 1994, and corresponding PCT ApplicationNo. PCT/US95/03125 filed Mar. 13, 1995, the disclosures of which areincorporated herein by reference.

Other BPI protein products useful according to the methods of theinvention are peptides derived from or based on BPI produced byrecombinant or synthetic means (BPI-derived peptides), such as thosedescribed in co-owned and copending PCT Application No. PCT/US94/10427filed Sep. 15, 1994, which corresponds to U.S. patent application Ser.No. 08/306,473 filed Sep. 15, 1994, and PCT Application No. US94/02465filed Mar. 11, 1994, which corresponds to U.S. patent application Ser.No. 08/209,762, filed Mar. 11, 1994, which is a continuation-in-part ofU.S. patent application Ser. No. 08/183,222, filed Jan. 14, 1994, nowabandoned, which is a continuation-in-part of U.S. patent applicationSer. No. 08/093,202, now abandoned, filed Jul. 15, 1993 (for which thecorresponding international application is PCT Application No.US94/02401 filed Mar. 11, 1994), which is a continuation-in-part of U.S.patent application Ser. No. 08/030,644 filed March 12, 1993, now U.S.Pat. No. 5,348,942, the disclosures of all of which are incorporatedherein by reference.

Presently preferred BPI protein products include recombinantly-producedN-terminal fragments of BPI, especially those having a molecular weightof approximately between 21 to 25 kD such as rBPI₂₃ or rBPI₂₁, ordimeric forms of these N-terminal fragments (e.g., rBPI₄₂ dimer).Additionally, preferred BPI protein products include rBPI₅₀ andBPI-derived peptides.

The administration of BPI protein products is preferably accomplishedwith a pharmaceutical composition comprising a BPI protein product and apharmaceutically acceptable diluent, adjuvant, or carrier. The BPIprotein product may be administered without or in conjunction with knownsurfactants, other chemothempeutic agents or additional knownanti-microbial agents. A preferred pharmaceutical composition containingBPI protein products (e.g., rBPI₅₀, rBPI₂₃) comprises the BPI proteinproduct at a concentration of 1 mg/ml in citmte buffered saline (5 or 20mM citrate, 150 mM NaCl, pH 5.0) comprising 0.1% by weight of poloxamer188 (Pluronic F-68, BASF Wyandotte, Parsippany, N.J.) and 0.002% byweight of polysorbate 80 (Tween 80, ICI Americas Inc., Wilmington,Del.). Another preferred pharmaceutical composition containing BPIprotein products (e.g., rBPI₂₁) comprises the BPI protein product at aconcentration of 2 mg/ml in 5 mM citrate, 150 mM NaCl, 0.2% poloxamer188 and 0.002% polysorbate 80. Such preferred combinations are describedin co-owned, co-pending PCT Application No. US94/01239 filed Feb. 2,1994, which corresponds to U.S. patent application Ser. No. 08/190,869filed Feb. 2, 1994, now U.S. Pat. No. 5,488,034, and U.S. patentapplication Ser. No. 08/012,360 filed Feb. 2, 1993, now abandoned, thedisclosures of all of which are incorporated herein by reference.

Suitable antibiotics, and therapeutically effective concentrationsthereof when administered with BPI protein products, may be determinedin in vivo models or according to in vitro tests, for example, the invitro minimum inhibitory concentration (MIC) and in vivo mouseperitonitis or rabbit bacteremia assays taught herein. Suitableantibiotics are antibiotics that act on the bacterial cell wall, cellmembrane, protein metabolism or nucleic acid metabolism. These wouldinclude antibiotics or combinations of antibiotics from the followingclasses: β-lactam antibiotics with or without β-lactamase inhibitors,aminoglycosides, tetracyclines, sulfonamides and trimethoprim,vancomycin, macrotides, fluoroquinolones and quinolones, polymyxins, andother antibiotics. Dosage and administration of suitable antibiotics areknown in the art, and briefly summarized below.

PENICILLINS

When a BPI protein product is concurrently administered with apenicillin, for treatment of a gram-negative bacterial infection, theBPI protein product is generally given parenterally in doses rangingfrom 1 μg/kg to 100 mg/kg daily, and preferably at doses ranging from 1mg/kg to 20 mg/kg daily. The penicillin is generally given in dosesranging from 1 mg/kg to 750 mg/kg daily, preferably not to exceed 24grams daily for adults (or 600 mg/kg daily for children), and ispreferably administered as follows:

Penicillin G is preferably administered parenterally to adults in dosesranging from 600,000 to 1,000,000 units per day. In conventionaladministration, it is effective largely against gram-positive organisms.For treatment of pneumococcal meningitis, penicillin G is administeredin doses of 20-24 million units daily, in divided doses every 2 or 3hours. For children, the preferred parenteral dose of penicillin G is300,000 to 1,000,000 units per day. One unit of penicillin G contains0.6 μg of pure sodium penicillin G (i.e., 1 mg is 1667 units).

Amoxicillin may be administered parenterally to adults in doses rangingfrom 750 mg to 1.5 grams per day, in 3 equally divided doses. Forchildren, preferred parenteral doses of amoxicillin range from 20 to 40mg/kg per day in 3 equally divided doses. Amoxicillin is also availablein combination with clavulanic acid, a β-lactamase inhibitor. A 250 mgdose of the combination drug amoxicillin/clavulanate will contain 250 mgof amoxicillin and either 125 or 62.5 mg of clavulanic acid. Thecombination is preferably administered to adults orally in doses of 750mg per day divided into 3 equal doses every 8 hours, with a preferreddose of 1.5 grams per day for severe infections, given in 3 equallydivided doses. In children, the preferred oral dose is 20 to 40 mg/kgper day in 3 equally divided doses.

Ampicillin is preferably administered parenterally to adults in doses of6 to 12 grams per day for severe infections, in 3 to 4 equally divideddoses. In children, the preferred parenteral dose of ampicillin is 50 to200 mg/kg per day in 3 to 4 equally divided doses. Larger doses of up to400 mg/kg per day, for children, or 12 grams per day, for adults, may beadministered parenterally for treatment of meningitis. Ampicillin isalso available in combination with sulbactam, a β-lactamase inhibitor.Each 1.5 gram dose of ampicillin/sulbactam contains 1 gram of ampicillinand 0.5 grams of sulbactam. The combination is preferably administeredparenterally to adults in doses of 6 to 12 grams per day divided into 4equal doses every 6 hours, not to exceed a total of 12 grams per day.

Azlocillin is preferably administered parenterally to adults in doses of8 to 18 grams per day, given in 4 to 6 equally divided doses.

Carbenicillin is preferably administered parenterally to adults in dosesof 30 to 40 grams per flay, given by continuous infusion or in 4 to 6equally divided doses. Daily doses of up to 600 mg/kg have been used totreat children with life-threatening infections.

Mezlocillin is preferably administered to adults parenterally in dosesof 100 to 300 mg/kg per day, given in 4 to 6 equally divided doses. Theusual dose is 16 to 18 grams per day; for life threatening infections,350 mg/kg per day may be administered, but in doses not to exceed 24grams per day given in 6 equally divided doses every 4 hours. Forchildren, the preferred parenteral dose of mezlocillin is 150 to 300mg/kg per day.

Nafcillin is preferably administered intravenously to adults in doses of3 grams per day, given in 6 equally divided doses every 4 hours, withdoubled doses for very severe infections. In conventionaladministration, it is effective largely against gram-positive organisms.In children, the preferred parenteral dose is 20 to 50 mg/kg per day, in2 equally divided doses every 12 hours. The preferred oral dose fornafcillin ranges from 1 gram per day to 6 grams per day in 4 to 6divided doses.

Oxacillin is preferably administered parenterally to adults in doses of2 to 12 grams per day, in 4 to 6 equally divided doses. In conventionaladministration, it is effective largely against gram-positive organisms.In children, oxacillin is preferably administered in doses of 100 to 300mg/kg per day.

Piperacillin is preferably administered parenterally to adults in dosesranging from 100 mg/kg, or 6 grams per day, in 2 to 4 equally divideddoses, up to a maximum of 24 grams per day, in 4 to 6 equally divideddoses. Higher doses have been used without serious adverse effects.

Ticarcillin is preferably administered parenterally to adults in dosesranging from 4 grams per day to 18 grams per day administered in 4 to 6equally divided doses. The usual dose is 200 to 300 mg/kg per day. Forchildren, the preferred parenteral dose of ticarcillin ranges from 50mg/kg per day to 300 mg/kg per day, given in 3, 4 or 6 equally divideddoses. The combination ticarcillin/clavulanate is preferablyadministered parenterally to adults in doses of 200 to 300 mg/kg per day(based on ticarcillin content), in 4 to 6 equally divided doses. Foradults, the usual dose is 3.1 grams (which contains 3 grams ofticarcillin and 100 mg of clavulanic acid) every 4 to 6 hours. Thecombination is also available in a dose of 3.2 grams, which contains 3grams of ticarcillin and 200 mg of clavulanic acid.

In general, it is desirable to limit each intramuscular injection of apenicillin or cephalosporin to 2 grams; larger doses should beadministered by multiple injections in different large muscle masses.

CEPHALOSPORINS

When a BPI protein product is concurrently administered with acephalosporin, for treatment of a gram-negative bacterial infection, theBPI protein product is generally given parenterally in doses rangingfrom 1/ μg/kg to 100 mg/kg daily, and preferably at doses ranging from 1mg/kg to 20 mg/kg daily. The cephalosporin is generally given in dosesranging from 1 μg/kg to 500 mg/kg daily, preferably not to exceed 16grams daily, and is preferably administered as follows:

Cefamandole is preferably administered parenterally to adults in dosesranging from 1.5 grams per day, given in 3 equally divided doses every 8hours, to 12 grams per day for life-threatening infections, given in 6equally divided doses every 4 hours. In children, cefamandole ispreferably administered in doses ranging from 50 to 150 mg/kg per day,in 3 to 6 equally divided doses, not to exceed a total of 12 grams perday.

Cefazolin is preferably administered parenterally to adults in doses of750 mg per day, given in 3 equally divided doses every 8 hours. Insevere, life-threatening infections, it may be administered at doses of6 grams per day divided into 4 equal doses every 6 hours; in rareinstances, up to 12 grams per day have been used. In children, thepreferred parenteral dose of cefazolin is 20 to 50 mg/kg per day,divided into 3 or 4 equal doses, with 100 mg/kg per day administered forsevere infections.

Cefonicid is preferably administered parenterally to adults in dosesranging from 500 mg once daily, to 2 grams once daily forlife-threatening infections. For intramuscular administration, a 2 gramdose should be divided into two 1-gram injections.

Cefoperazone is preferably administered parenterally to adults in dosesranging from 2 grams per day, given in 2 equally divided doses every 12hours, to 12 grams per day for severe infections, given in 2, 3 or 4equally divided doses. Doses up to 16 grams per day have beenadministered without complications.

Cefotetan is preferably administered parenterally to adults in doses of1 to 4 grams per day, in 2 equally divided doses every 12 hours.Cefotetan may be administered in higher doses for life-threateninginfections, not to exceed a total dose of 6 grams per day.

Cefotaxime is preferably administered parenterally to adults in dosesranging from 1 to 12 grams per day, not to exceed 12 grams per day (2grams every 4 hours) for life-threatening infections. In children, theparenteral dose of cefotaxirne is preferably 50 to 180 mg/kg, dividedinto 4 to 6 equal doses.

Cefoxitin is preferably administered parenterally to adults in dosesranging from 3 to 12 grams per day, given in 3, 4, or 6 equally divideddoses. In children, cefoxitin is preferably administered parenterally indoses of 80 to 160 mg/kg per day, given in 4 or 6 equally divided doses,not to exceed a total dose of 12 grams per day.

Ceftazidime is preferably administered parenterally to adults in dosesranging from 500 mg per day, given in 2 to 3 equally divided doses(every 8 or 12 hours), up to a maximum of 6 grams per day. In children,ceftazidime is preferably administered intravenously in doses of 30 to50 mg/kg, to a maximum of 6 grams per day.

Ceftizoxime is preferably administered parenterally to adults in dosesranging from 1 gram per day, given in 2 equally divided doses every 12hours, to 12 grams per day for life-threatening infections, given in 3equally divided doses every 8 hours. The usual adult dose is 1 to 2grams every 8 or 12 hours. For children, the preferred parenteral doseis 50 mg/kg every 6 or 8 hours, for a total daily dose of 200 mg/kg.

Ceftriaxone is preferably administered parenterally to adults in dosesranging from 1 to 2 grams per day, given in 2 equally divided dosesevery 12 hours. It may be given in higher doses, not to exceed a totalof 4 grams per day. In children, the preferred parenteral dose ofceftriaxone is 50 to 75 mg/kg per day, not to exceed 2 grams per day. Inmeningitis, ceftriaxone may be administered in doses of 100 mg/kg perday, not to exceed 4 grams per day.

Cefuroxime is preferably administered parenterally to adults in dosesranging from 2.25 to 4.5 grams per day, in 3 equally divided doses every8 hours. For life-threatening infections, 6 grams per day may beadministered in 4 equally divided doses every 6 hours, and formeningitis, 9 grams per day may be administered in 3 equally divideddoses every 8 hours. For children, the preferred parenteral dose ofcefuroxime is 50 to 150 mg/kg per day in 3 to 4 equally divided doses,or 240 mg/kg per day for meningitis.

Cephalexin is formulated for oral administration, and is preferablyadministered orally to adults in doses ranging from 1 to 4 grams per dayin 2 to 4 equally divided doses. For children, the preferred dose is 20to 50 mg/kg per day in divided doses, with doses being doubled forsevere infections.

Cephalothin is usually administered parenterally to adults in doses of 8to 12 grams per day.

OTHER BETA-LACTAMS

When a BPI protein product is concurrently administered with an imipenemantibiotic, for treatment of a gram-negative bacterial infection, theBPI protein product is generally given parenterally in doses rangingfrom 1 μg/kg to 100 mg/kg daily, and preferably at doses ranging from 1mg/kg to 20 mg/kg daily. The imipenem is generally given in dosesranging from 1 μg/kg to 100 mg/kg daily, and is preferably administeredas follows:

Imipenem is available in combination with cilastatin, an inhibitor ofthe renal dipeptidase enzyme that rapidly inactivates imipenem. Thecombination is preferably administered intramuscularly to adults indoses of 1 to 1.5 grams per day, given in 2 equally divided doses every12 hours. Intramuscular doses exceeding 1.5 grams per day are notrecommended. The combination is preferably administered intravenously indoses ranging from 1 to 4 grams per day, in 4 equally divided dosesevery 6 hours; doses exceeding 50 mg/kg per day, or 4 grams per day, arenot recommended.

When a BPI protein product is concurrently administered with amonobactam antibiotic, for treatment of a gram-negative bacterialinfection, the BPI protein product is generally given parenterally indoses ranging from 1 μg/kg to 100 mg/kg daily, and preferably at dosesranging from 1 mg/kg to 20 mg/kg daily. The monobactam is generallygiven in doses ranging from 1 μg/kg to 200 mg/kg daily, and ispreferably administered as follows:

Aztreonam is preferably administered parenterally to adults in dosesranging from 1 gram per day, given in 2 equally divided doses every 12hours, up to a maximum recommended dose of 8 grams per day in cases oflife-threatening infection, given in 3 or 4 equally divided doses.

AMINOGLYCOSIDES

When a BPI protein product is concurrently administered with anaminoglycoside, for treatment of a gram-negative bacterial infection,the BPI protein product is generally given parenterally in doses rangingfrom 1 μg/kg to 100 mg/kg daily, and preferably at doses ranging from 1mg/kg to 20 mg/kg daily. The aminoglycoside is generally given in dosesranging from 1 μg/kg to 20 mg/kg daily, preferably not to exceed 15mg/kg daily, and is preferably administered as follows:

When administering aminoglycosides, it is desirable to measure serumpeak and trough concentrations to ensure the adequacy and safety of thedosage. Dosages should generally be adjusted to avoid toxic peak andtrough concentrations. Amikacin is preferably administered parenterallyto adults and children in doses of 15 mg/kg per day, divided into two orthree equal doses every 8 or 12 hours, and not to exceed a total dose of1.5 grams per day. For uncomplicated infections, a dose of 500 mgamikacin per day, in 2 equally divided doses, may be administered.Dosages should be adjusted to avoid prolonged serum peak concentrationsof amikacin above 35 μg/ml and prolonged trough concentrations greaterthan 10 μg/ml.

Gentamicin is preferably administered parenterally to adults in doses of3 mg/kg per day, in three equally divided doses every 8 hours. Forlife-threatening infections, up to 5 mg/kg per day in 3 to 4 equallydivided doses may be administered, but this dosage should be reduced to3 mg/kg per day as soon as clinically indicated. For children,gentamicin is preferably administered parenterally in doses of 6 to 7.5mg/kg per day. Dosages should be adjusted to avoid prolonged serum peakconcentrations of gentamicin above 12 μg/ml and prolonged troughconcentrations greater than 2 μg/ml.

Netilmicin may be administered parenterally to adults in doses rangingfrom 3 mg/kg per day, in 2 equally divided doses every 12 hours, to 6.5mg/kg per day for serious systemic infection, in 2 or 3 equally divideddoses. In children, the preferred parenteral dose is 5.5 to 8 mg/kg perday, in 2 or 3 equally divided doses. Dosages should be adjusted toavoid prolonged serum peak concentrations of netilmicin above 16 μg/mland prolonged serum trough concentrations above 4 μg/ml.

Tobramycin is preferably administered parenterally to adults in doses of3 mg/kg per day, given in three equally divided doses every 8 hours. Forlifethreatening infections, tobramycin may be administered in doses upto 5 mg/kg per day, in 3 or 4 equally divided doses, but this dosageshould be reduced to 3 mg/kg per day as soon as clinically indicated. Inchildren, tobramycin is preferably administered parenterally in doses of6 to 7.5 mg/kg per day. Prolonged serum concentrations of tobramycinabove 12 μg/ml should be avoided, and rising trough levels above 2 μg/mlmay indicate tissue accumulation, which may contribute to toxicity.

Concurrent administration of BPI protein product with theaminoglycosides, including amikacin, gentamicin, netilmicin andtobramycin, may permit a lowering of the dose of these toxic antibioticsnecessary to achieve a therapeutic effect.

TETRACYCLINES

When a BPI protein product is concurrently administered with atetracycline, for treatment of a gram-negative bacterial infection, theBPI protein product is generally given parenterally in doses rangingfrom 1 μg/kg to 100 mg/kg daily, and preferably at doses ranging from 1mg/kg to 20 mg/kg daily. The tetracycline is generally given in dosesranging from 1 μg/kg to 50 mg/kg daily, and is preferably administeredas follows:

The tetracycline antibiotics are generally administered to adults indoses of 1 to 2 grams per day. An exception is doxycycline, which ispreferably administered intravenously to adults in doses of 100 to 200mg per day, and to children in doses of 2 mg/lb per day. Tetracyclinemay be administered parenterally to adults in doses of 0.5 to 2 gramsper day, in 2 equally divided doses, and to children in doses of 10 to20 mg/kg per day.

SULFONAMIDES

When a BPI protein product is concurrently administered with asulfonamide or trimethoprim, for treatment of a gram-negative bacterialinfection, the BPI protein product is generally given parenterally indoses ranging from 1 μg/kg to 100 mg/kg daily, and preferably at dosesranging from 1 mg/kg to 20 mg/kg daily. The sulfonamide or trimethoprimis generally given in doses ranging from 1 μg/kg to 150 mg/kg daily,preferably not to exceed a combination dose of 960 mg trimethoprim/4.8gsuffamethoxazole daily, and is preferably administered as follows:

The combination trimethoprim/sulfamethoxazole is available in aformulation containing a 1:5 ratio of tfimethoprim and sulfamethoxazole(e.g., 16 mg trimethoprim and 80 mg sulfamethoxazole). The combinationis preferably administered intravenously to adults or children in dosesof 8 to 10 mg/kg (based on the weight of the trimethoprim component) perday, in 2 to 4 equally divided doses. For Pneumocysas carinii infection,the combination can be administered in doses of 20 mg/kg (based on theweight of the trimethoprim component) per day, in 3-4 equally divideddoses, to a maximum recommended dose of 960 mg trimethoprim/4.8 gsuffamethoxazole per day. Trimethoprim alone is preferably administeredorally to adults in doses of 200 mg per day. Sulfamethoxazole alone ispreferably administered orally to adults in doses of 2 to 3 grams perday, and to children orally in doses of 50 to 60 mg/kg per day.

FLUOROQUINOLONES

When a BPI protein product is concurrently administered with afiuoroquinolone or quinolone, for treatment of a gram-negative bacterialinfection, the BPI protein product is generally given parenterally indoses ranging from 1 μg/kg to 100 mg/kg daily, and preferably at dosesranging from 1 mg/kg to 20 mg/kg daily. The fluoroquinolone or quinoloneis generally given in doses ranging from 1 μg/kg to 50 mg/kg daily,preferably not to exceed 1 gram daily, and is preferably administered asfollows:

Norfloxacin is preferably administered orally to adults in doses from400 to 800 mg daily, divided into two doses every 12 hours. Cinoxacin ispreferably administered orally to adults in doses of 1 gram per day,given in 2 or 4 equally divided doses. Ciprofloxacin is preferablyadministered to adults intravenously in doses from 400 to 800 mg daily,or orally in doses from 500 to 1500 mg daily, divided into two dosesevery 12 hours. Ofioxacin is preferably administered to adultsintravenously in doses from 400 to 800 mg daily, or orally in doses from400 to 800 mg daily, divided into two doses every 12 hours.

VANCOMYCIN

When a BPI protein product is concurrently administered with vancomycin,for treatment of a gram-negative bacterial infection, the BPI proteinproduct is generally given parenterally in doses ranging from 1 μg/kg to100 mg/kg daily, and preferably at doses ranging from 1 mg/kg to 20mg/kg daily. The vancomycin is generally given in doses ranging from 1mg/kg to 50 mg/kg daily, and is preferably administered parenterally toadults in doses of 2 grams per day, divided into 2 or 4 doses every 6 or12 hours. In children it is preferably administered in doses of 40mg/kg, given in 4 equally divided doses every 6 hours. In conventionaladministration, vancomycin is effective largely against gram-positiveorganisms.

MACROLIDES

When a BPI protein product is concurrently administered with amacrolide, for treatment of a gram-negative bacterial infection, the BPIprotein product is generally given parenterally in doses ranging from 1μg/kg to 100 mg/kg daily, and preferably at doses ranging from 1 mg/kgto 20 mg/kg daily. The macrolide is generally given in doses rangingfrom 1 μg/kg to 100 mg/kg daily, and is preferably administered asfollows:

Erythromycin is preferably administered intravenously to adults andchildren in doses of 15 to 20 mg/kg per day, given by continuousinfusion or in 4 equally divided doses every 6 hours. Erythromycin canbe administered at doses up to 4 grams per day in cases of very severeinfection.

Clarithromycin is preferably administered orally to adults in doses of500 mg to 1 gram daily, in equally divided doses every 12 hours.

Azithromycin is preferably administered orally to adults at a dose of500 mg on the first day of treatment followed by 250 mg once daily for 4days, for a total dose of 1.5 grams.

OTHERS

When a BPI protein product is concurrently administered with otherantibiotics, for treatment of a gram-negative bacterial infection, theBPI protein product is generally given parenterally in doses rangingfrom 1 μg/kg to 100 mg/kg daily, and preferably at doses ranging from 1mg/kg to 20 mg/kg daily.

Polymyxin B is generally given in doses ranging from 1 unit/kg to 45,000units/kg daily, and is preferably administered intravenously to adultsand children in doses of 15,000 to 25,000 units/kg per day, divided into2 equal doses every 12 hours. It may be administered intramuscularly indoses of 25,000 to 30,000 units/kg per day, although these injectionsare very painful. Doses of polymyxin B as high as 45,000 units/kg perday have been used in limited clinical studies to treat neonates forPseudomonas aeruginosa sepsis. Polymyxin B is the treatment of choicefor P. aeruginosa meningitis, and is preferably administeredintrathecally to adults and older children in doses of 50,000 units oncedaily for 3 to 4 days, followed by 50,000 units every other day; inchildren under two years old, it is administered intrathecally in dosesof 20,000 daily for 3 to 4 days, followed by 25,000 units every otherday.

Chloramphenicol is preferably administered intravenously to adults indoses of 50 mg/kg per day, in 4 equally divided doses; in exceptionalcases, it can be administered in doses up to 100 mg/kg per day. Inchildren, chloramphenicol is preferably administered intravenously indoses of 25 mg/kg per day, although up to 100 mg/kg per day can beadministered in cases of severe infection.

Clindamycin is preferably administered parenterally to adults in dosesranging from 600 mg to 4.8 grams per day, given in 2, 3 or 4 equallydivided doses. It is recommended that the dose in each intramuscularinjection not exceed 600 mg. For children, clindamycin is preferablyadministered parenterally in doses of 15-40 mg/kg per day, given in 3 or4 equally divided doses.

Dosages of all antimicrobial agents should be adjusted in patients withrenal impairment or hepatic insufficiency, due to the reduced metabolismand/or excretion of the drugs in patients with these conditions. Dosesin children should also be reduced, generally according to body weight.Those skilled in the art can readily optimize effective dosages andadministration regimens for the BPI protein product and the antibioticsin concurrent administration.

Other aspects and advantages of the present invention will be understoodupon consideration of the following illustrative examples. Example 1addresses the bactericidal effect of gentamicin and BPI whenadministered to two different strains of E. coli. Example 2 addressesthe bactericidal effect of gentamicin and BPI for a number of othergram-negative strains. Example 3 addresses the bactericidal effect ofpolymyxin B and BPI when administered to two different strains of E.coli. Example 4 addresses the bactericidal effect of polymyxin B and BPIfor a number of other gram-negative strains. Example 5 addresses theeffect of a BPI protein product with a cephalosporin antibiotic in an invivo mouse peritonitis E. coli O111:B4 challenge model. Example 6 alsorelates to the effect of a BPI protein product with a cephalosporinantibiotic in an in vivo mouse peritonitis E. coli O111: B4 challengemodel. Example 7 relates to the effect of a BPI protein product with acephalosporin antibiotic in an in vivo mouse peritonitis E. coli O7:K1challenge model. Example 8 addresses the effect of a BPI protein productwith a cephalosporin antibiotic in an in vivo rabbit bacteremia E. coliO7:K1 challenge model. Example 9 addresses the effect of a BPI proteinproduct with an aminoglycoside antibiotic in an in vivo mouseperitonitis E. coli O7:K1 challenge model. Example 10 relates to theeffect of a BPI protein product in vitro on the antibioticsusceptibility of ceftriaxone-resistant gram-negative organisms.Examples 11-19 address large-scale screening of the antibioticsusceptibility-increasing effect of a BPI protein product on a varietyof gram-negative organisms: Pseudomonas aeruginosa and other Pseudomonasspecies (Example 11), E. coli (Example 12), Citrobacter (Example 13),Klebsiella (Example 14), Enterobacter (Example 15), Serratia (Example16), Proteus (Example 17), Providencia (Example 18), Morganella (Example19), Acinetobacter (Example 20), and Salmonella and Shigella (Example21). Example 22 examines the early in vitro bactericidal effect of BPIprotein product and selected antibiotics on E. coli J5, E. coli O7:K1,Enterobacter cloacae and Klebsiella pneumoniae. Example 23 examines theeffect of a variety of BPI protein products on several representativeorganisms, Acinetobacter anitratus, Enterobacter cloacae, and twostrains of E. coli. Example 24 relates to the screening of BPI peptidesfor antibacterial activity against E. coli. Example 25 addresses theeffect on E. coli O111:B4 of concurrent administration of BPI proteinproduct with tetracycline or gentamicin.

EXAMPLE 1 SYNERGISTIC BACTERICIDAL EFFECTS OF GENTAMICIN AND BPI:ADMENISTION TO E. COLI AND E. COLI 0111:B4 GRAM-NEGATIVE ORGANISMS

In this example, a micro dilution plate minimum inhibitory concentration(MIC) assay was conducted to determine the sensitivity of E. coliorganisms to the bactericidal effects of BPI protein productsconcurrently administered with the antibiotic gentamicin. The assayswere conducted against the BPI sensitive organism E. coli J5 (an Rcrough mutant of E. coli 0111:B4), and a BPI resistant organism E. coli0111:B4.

Specifically, organisms were grown overnight on blood agar plates at 37°C. in air, single colonies were then sub-cultured in 100 mL of nutrientbroth No. 2 (Oxoid CM67) and incubated with gentle agitation on anorbital shaker for 5 1/4 hours until in log phase. Fifty mL of thebacterial suspension was then spun down in a DenIcy BR401 benchcentrifuge at 4000 rpm for 15 minutes and the pellet was resuspended andwashed twice using sterile normal saline. Bacteria were then resuspendedin saline such that a 1:10 dilution had an optical density of 0.9(+/-0.01) at 325 nm (corresponding to approximately 4×10⁹ cells per mL)and diluted to give a final concentration of 4×10⁶ cells per mL in "BPImedia" (described below).

All assays and dilutions of BPI protein products and gentamicin wereperformed using "BPI media" consisting of 50% peptone water (Oxoid L37,Lot: 25851279) with 0.1M MOPS (Sigma M-1254) buffered to pH 6.00 withsodium hydroxide. This provides a nutritive media with a low protein anddivalent cation concentration adjusted to a pH which is not inhibitoryto bacterial growth and allows for readily measurable (though notoptimal) BPI activity.

rBPI₂₃ and gentamicin (Sigma G-1264, Lot: 91H00325) were diluted in BPImedia such that 100 μL of diluted BH, 50 μL of diluted gentamicin and 50μL of bacterial suspension in the final volume of 200 μL per well, gaveconcentrations in serial dilutions from 1000 nM (25 μg per mL) BPI and32 μg per mL of gentamicin with a fixed concentration of 10⁶ cells/mL.Checkerboards were then constructed in round boUomed 96 well microtitreplates (Greiner No. 650180) and incubated with non-sealing lids at 37°C. in air for 18 hours. Plates were then read by eye and in an automaticplate reader (Titretek Multiscan plus) at 580 nm with visible growthcorresponding to an optical density of approximately 0.1 (see Table 1for E. coli J5, and Table 3 for E. coli O111:134). Viable counts weremade from the wells adjacent to the cutoff of visible growth for the twoE. coli plates (see Table 2 for E. coli J5, and Table 4 for E. coli O111:B4) by dilution of 10 μL in 990 μL of Nutrient Broth No. 2 andspread plates were prepared with 25 μL on blood agar. The inhibitoryactivity of BPI protein product with antibiotic was evaluated by themethod of Eliopoulos and Moellering In Antibiotics in LaboratoryMedicine, 3rd ed. (Lorian, V., Ed.) pp. 432-492, Williams and Wilkins,Baltimore Md. (1991), wherein a fractional inhibitory concentrationindex (FIC) of less than 0.5 was scored as synergy, 1 was scored asadditive and greater than 1 but less than 2 was scored as indifferent.

A positive synergistic interaction was demonstrated between rBPI₂₃ andgentamicin using the BPI sensitive E. coli J5 with gentamicin at aconcentration of 0.25 μg per mL, reducing the MIC of BPI byapproximately eight-fold from 500 nM (12.5 μg per mL) to 62.5 nM (1.56μg per mL) with similar reductions of the minimum bactericidalconcentration (MBC).

                                      TABLE 1                                     __________________________________________________________________________    Visible Growth (bold line) of E. coli J5 and ODS (580 nm)                     __________________________________________________________________________    Gentamicin (μg per ml)                                                      ##STR1##                                                                            ##STR2##                                                               __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    Visible Growth (bold line) of E. coli J5 and Viable Counts                    __________________________________________________________________________    Gentamicin (μg per ml)                                                      ##STR3##                                                                            ##STR4##                                                               __________________________________________________________________________     Counts expressed as counts per ml,                                            NC = not counted,                                                             ++ = too numerous to count.                                              

                                      TABLE 3                                     __________________________________________________________________________    Visible Growth (bold line) of E. coli 0.111:B4 and ODS (580                   __________________________________________________________________________    nm)                                                                           Gentamicin (μg per ml)                                                      ##STR5##                                                                            ##STR6##                                                               __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________    Visible Growth (bold line) of E. coli 0.111:B4 and viable                     __________________________________________________________________________    counts                                                                        Gentamicin (μg per ml)                                                      ##STR7##                                                                            ##STR8##                                                               __________________________________________________________________________     Counts expressed as count per ml,                                             NC = not counted,                                                             ++ = too numerous to count.                                              

EXAMPLE 2 SYNERGISTIC BACTERICIDAL EFFECTS OF GENTAMICIN AND BPI:ADMINISTRATION TO ADDITIONAL GRAM-NEGATIVE ORGANISMS

In this example, micro dilution plate MIC assays were conductedaccording to the method of Example 1 to determine the sensitivity of avariety of gram-negative organisms to the cytotoxic effects of BPIprotein products concurrently administered with gentamicin antibiotic.The results of those assays axe shown in Table 5 below. Positivesynergistic bactericidal interactions were observed against E. coli J5,E. coli 01:K1, E. coli (S2252), K. oxytoca, E. tarda, Salmonellatyphimurium (S2136) and Salmonella arizonae. Possible synergisticbactericidal interactions (indicated as "additive (+)") were observedagainst E. cloacae (10005), E. gergoviae (11434), P. aeruginosa (10332)and P. aeruginosa (10662). The concurrent administration of gentamicinand rBPI₂₃ had only additive, indifferent or indeterminate effectsagainst the other tested gram-negative bacteria.

                                      TABLE 5                                     __________________________________________________________________________    MIC Values and Results of Checkerboard Susceptibility Testing With BPI        and Gentamicin                                                                                MIC of Single                                                                         MIC of Single                                                                          Lowest MIC of the                                            Agent BPI.sub.23                                                                      Agent Gentamicin                                                                       Agents Together                                                                         Interpretation                     Organism (NCTC) (nM)    (μg/ml)                                                                             rBPI.sub.23 /Gentamicin                                                                 (Gentamicin)                       __________________________________________________________________________    E. coli J5      250     1.0        62.5/0.125                                                                            synergy                            E. coli 01:K1   >2000   2.0       31/0.5   synergy                            E. coli (S2252) NCTC 10418                                                                    500     0.5       250/0.25 additive/synergy                   E. coli 0111:B4 >2000   1.0      >2000/1.0 indifferent                        E. coli (S2216) >500    1.0      >500/1.0  indifferent                        E. coli H262    >500    --       --        indifferent                        E. dispar (S2162)                                                                             >500    --       --        indifferent                        E. alcalescens (S2196)                                                                        >2000   --       --        indifferent                        K. oxytoca      >2000   1.0       1000/0.25                                                                              synergy                            K. pneumoniae   >2000   0.5      >2000/0.5 indifferent                        E. cloacae (10005)                                                                            >2000   1.0      1000/0.5  additive (+)                       E. gergoviae (11434)                                                                          >2000   2.0      2000/0.5  additive (+)                       S. marcescens (10211)                                                                         >2000   4.0      >2000/4.0 indifferent                        P. rettgeri (S2253)                                                                           >500    2.0      1000/1.0  indifferent                        P. vulgaris (4175)                                                                            500     0.25       250/0.125                                                                             additive                           P. morganii (S2161)                                                                           >2000   2.0      2000/2.0  indifferent                        P. aeruginosa (10332)                                                                         >2000   0.5        31/0.25 additive (+)                       P. aeruginosa (840P)                                                                          >2000   1.0      >2000/1.0 indifferent                        P. aeruginosa (10662)                                                                         >2000   0.25      2000/0.125                                                                             additive (+)                       P. aeruginosa (U600)                                                                          >2000   0.5        62.5/0.25                                                                             indifferent                        K. aerogenes NCTC 9496                                                                        >2000   1.0      2000/0.5  indifferent                        Shigella dysenteriae NCTC 4837                                                                >2000   1.0      >2000/1.0 indifferent                        E. tarda        500     1.0        31/0.125                                                                              synergy                            K. rhinoscleromatis                                                                           >500    1.0      >500/1.0  indifferent                        Salmonella choleresuis                                                                        >2000   --       --        indifferent                        Salmonella typhimurium (S2185)                                                                >500    0.25     >500/0.25 indifferent                        Salmonella typhimurium (S2136)                                                                >2000   >4.0      31/4.0   synergy                            Salmonella arizonae                                                                           >500    1.0      --        synergy                            E. aerogenes (S2164)                                                                          >2000   1.0       62.5/1.0 indifferent                        C. freundi      >2000   --       --        indifferent                        __________________________________________________________________________     (+) possibility of synergy but FIC incalculable because rBPI.sub.23 MIC       outside tested concentration range.                                      

EXAMPLE 3 SYNERGISTIC BACTERICIDAL EFFECTS OF POLYMYXIN B AND BPI:ADMINISTATION TO E. COLI J5 AND E. COLI 0111:B4 GRAM-NEGATIVE ORGANISMS

In this example, micro dilution plate MIC assays were conductedaccording to the method of Example 1 to determine the sensitivity of E.coli J5 and E. coli 0111:B4 to the cytotoxic effects of BPI proteinproducts concurrently administered with the antibiotic polymyxin B.Polymyxin B solution with an activity of 10240 units/mL was prepared bypreparing a solution of 1.595 mg of polymyxin B sulfate stock powder permL, and diluting it in sterile water for injection as 20 μg in 12.54 mL.

A positive synergistic interaction was demonstrated between rBPI₂₃ andpolymyxin B using E. coli 0111:B4 (see Tables 8 and 9) but theadministration of polymyxin B with BPI did not have synergisticbactericidal effects with BPI when applied to E. coli J5 as illustratedby the results shown in Tables 6 and 7.

                                      TABLE 6                                     __________________________________________________________________________    Visible Growth (bold line) of E. coli J5 and ODS (580 nm)                     Polymyxin B (μg/ml)                                                        __________________________________________________________________________     ##STR9##                                                                            ##STR10##                                                              __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________    Visible Growth (bold line) of E. coli J5 and Viable                           Counts Polymyxin B (μg/ml)                                                 __________________________________________________________________________     ##STR11##                                                                           ##STR12##                                                              __________________________________________________________________________     Counts expressed as counts per ml,                                            NC = not counted,                                                             ++ = too numerous to count.                                              

                                      TABLE 8                                     __________________________________________________________________________    Visible Growth (bold line) of E. coli 0111:B4 and ODS (580                    __________________________________________________________________________    nM)                                                                           Polymyxin B (μg/ml)                                                         ##STR13##                                                                           ##STR14##                                                              __________________________________________________________________________

                                      TABLE 9                                     __________________________________________________________________________    Visible Growth (bold line) of E. coli 0111:B4 and Viable                      __________________________________________________________________________    Counts                                                                        Polymyxin B (μg/ml)                                                         ##STR15##                                                                           ##STR16##                                                              __________________________________________________________________________     Counts expressed as counts per ml,                                            NC = not counted,                                                             ++ = too numerous to count.                                              

EXAMPLE 4 SYNERGISTIC BACTERICIDAL EFFECTS OF POLYMYXIN B AND BPI:ADMINISTRATION TO ADDITIONAL GRAM-NEGATIVE ORGANISMS

In this example, micro dilution MIC assays were conducted according tothe method of Example 1 to determine the sensitivity of a variety ofgram-negative organisms to the cytotoxic effects of BPI protein productsconcurrently administered with polymyxin B antibiotic. The results ofthose assays are shown in Table 10 below.

These assay results show additive or synergistic effects with the use ofpolymyxin B at concentrations of 0.3 μg/mL, a level of which is 10-20times lower than when that antibiotic is used conventionally.

                                      TABLE 10                                    __________________________________________________________________________    MIC Values and Results of Checkerboard Susceptibility Testing With BPI        and Polymyxin B (PB)                                                                                           Lowest MIC of the                                          MIC of Single                                                                          MIC of Single                                                                           Agents Together                                                                         Interpretation                     Organism (NCTC)                                                                             Agent BPI.sub.23 (nM)                                                                  Agent PB (μg/ml)                                                                     rBPI.sub.23 /PB                                                                         (Polymyxin B)                      __________________________________________________________________________    E. coli J5    250      2.5       250/2.5   indifferent                        E. coli (S2252) NCTC 10418                                                                  500      5.0       250/2.5   indifferent                        E. coli 0111:B4                                                                             >2000    5.0       250/2.5   synergy                            E. cloacae (10005)                                                                          >500     0.5       500/0.5   indifferent                        E. gergoviae (11434)                                                                        >2000    5.0       125/2.5   additive (+)                       S. marcescens (10211)                                                                       >2000    >10.0     >2000/10.0                                                                              indifferent                        P. rettgeri (S2253)                                                                         >2000    2.5        125/1.25 synergy                            P. aeruginosa (10332)                                                                       >2000    1.25      250/0.6   synergy                            P. aeruginosa (840P)                                                                        >2000    1.25      1000/0.6  synergy                            P. aeruginosa (10662)                                                                       >2000    1.25      125/0.6   synergy                            P. aeruginosa (U600)                                                                        >2000    1.25      2000/0.3  synergy                            E. aerogenes (S2164)                                                                        >2000    >10.0     >2000/10.0                                                                              indifferent                        __________________________________________________________________________

EXAMPLE 5 SYNERGISTIC EFFECTS OF CEFAMANDOLE AND BPI PROTEIN PRODUCT INVIVO IN MICE CHALLENGED INTRAPERITONEALLY WITH LIVE E. COLI 0111:B4BACTERIA: EFFECT ON SURVIVAL

In this example, the protective effect of cefamandole nafate antibiotic(MANDOL®, Lilly) a semisynthetic broad-spectrum cephalosporin antibioticwith and without a BPI protein product was evaluated by means ofchallenging ICR mice with an LD₉₀₋₁₀₀ dose level of live E. coli 0111:B4bacteria, a strain that is not susceptible to the bactericidal/growthinhibitory effects of BPI protein product. Specifically, four groups of15 ICR mice were treated such that each ICR mouse received an injectionof bacteria (1.8×10⁹ CFU/mouse) intraperitoneally; an intraperitonealinjection of cefamandole nafate (MANDOL®, 100 mg/kg) or saline; and thenan intrapefitoneal injection of rBPI₂₁ (500 μg/mouse) or BPI buffer.Survival of the mice was then evaluated over a period of 7 days with theresults illustrated in FIG. 1.

Concurrent administration of BPI protein product with cefamandole, oradministration of cefamandole alone, showed significant protection inmice challenged with E. coli 0111:B4 when compared to the buffer control(p≦0.001 and p≦0.05 respectively). The protective effect of the BPIprotein product when administered without cefamandole was not evident.When compared to treatment with cefamandole alone, concurrentadministration of BPI protein product with cefamandole showed improvedprotection at p≦0.1. These results indicate that the concurrentadministration of cefamandole and a BPI protein product has synergistictherapeutic effects against E. coli 0111:B4.

EXAMPLE 6 SYNERGISTIC EFFECTS OF CEFAMANDOLE AND BPI PROTEIN PRODUCT INVIVO IN MICE CHALLENGED INTRAPERITONEALLY WITH LIVE E. COLI 0111:B4BACTERIA: EFFECT ON SURVIVAL AND ON BACTERIAL CLEARANCE FROM BLOOD ANDPERITONEAL LAVAGE FLUID

The protective effects of a cephalosporin antibiotic and a BPI proteinproduct were evaluated in mice challenged intrapefitoneally with E. coli0111:B4, a strain that is resistant to the bactericidal effects of BPIprotein product. The assay was conducted using the following procedure.Male ICR mice (Simonsen Laboratories, Gilroy Calif.), 5-7 weeks old,were housed under controlled climate and dark/light cycles and wereallowed free access to food and water. Mice received an intraperitonealinjection of 0.5 ml of bacteria in doses near an LD₉₀ (2×10⁹ CFU/mouse).Immediately after bacterial challenge the animals received anintraperitoneal injection of (1) vehicle only, (2) 500 μg/mouse rBPI₂₁and vehicle, (3) 100 mg/kg cefamandole nafate (Mandol® in phosphatebuffered saline; Eli Lilly, Indianapolis, Ind.) and vehicle, or (4) 500μg rBPI₂₁ and 100 mg/kg cefamandole.

Survival of the four groups was monitored for 7 days. Survival data wasstatistically analyzed using the Chi-square test. In a separateexperiment using a bacterial challenge of 2.5×10⁹ CFU E. coli O 111:B4,blood and peritoneal lavage fluid were collected for culture atdifferent time points following bacterial challenge. Blood was obtainedfrom the retro-orbital sinus. At least 1 ml of peritoneal lavage fluidwas obtained after intraperitoneal injection of 3 ml of phosphatebuffered saline. Bacterial counts (expressed as CFU/ml) were determinedby inoculating trypticase soy agar plates with 10-fold dilutions ofblood or peritoneal lavage samples, incubating the plates overnight at37° C., and counting the colonies. Statistical comparisons of this datawere performed with the analysis of variance.

FIG. 2 shows effects on survival of cefamandole (100 mg/kg), rBPI₂₁ (500μg) or the concurrent administration of the two agents. The BPI proteinproduct alone had no effect, while cefamandole treatment alone increasedsurvival, although not significantly. In contrast, the concurrentadministration of rBPI₂₁ with cefamandole resulted in a significantincrease in survival (p<0.05) above that achieved by either treatmentalone. FIGS. 3 and 4 show that rBPI₂₁ alone failed to reduce counts ineither peritoneal lavage fluid or blood after challenge with bacteria,while cefamandole treatment alone significantly reduced counts in both(p<0.01 vs. vehicle). However, the concurrent administration of rBPI₂₁and cefamandole reduced bacterial counts in the peritoneal lavage fluidby more than two orders of magnitude below that achieved by cefamandolealone (p<0.01 of concurrent administration vs. cefamandole only) at the2 and 6 hour time points, and entirely eliminated counts after 24 hours.Blood of mice that received concurrent administration of rBPI₂₁ andcefamandole was completely free of bacteria at all time points.

Thus, the concurrent administration of a BPI protein product, rBPI₂₁,with a suboptimal dose of a cephalosporin antibiotic, cefamandole,resulted in a superior therapeutic effect. The data indicates that BPIprotein products and cephalosporin antibiotics produce a synergistictherapeutic effect. Since cefamandole alone reduced counts byapproximately two orders of magnitude compared to vehicle-treatedanimals, another experiment was conducted to determine if rBPI₂₁ alonereduced bacterial counts when the inoculum was reduced to 10⁷ CFU. Datafrom this experiment showed that rBPI₂₁ (500 μg) did not significantlyreduce bacterial counts in blood or peritoneal lavage fluid after achallenge of 10⁷ CFU. This suggests that an antibiotic-mediatedreduction in the magnitude of the bacterial count cannot, in itself,explain the protection associated with concurrent administration of BPIprotein product and antibiotic.

EXAMPLE 7 SYNERGISTIC EFFECTS OF CEFAMANDOLE AND BPI PROTEIN PRODUCT INVIVO IN MICE CHALLENGED INTRAPERITONEALLY WITH LIVE E. COLI O7:K1BACTERIA: EFFECT ON SURVIVAL

The protective effects of a cephalosporin antibiotic and a BPI proteinproduct were evaluated in mice challenged intraperitoneally with E. coliO7:K1 (ATCC Accession No. 23503), a strain that is susceptible to thebactericidal effects of BPI protein product. The general proceduredescribed above in Example 5 was followed. Four groups of 20 mice werechallenged intraperitoneally with 2×10⁷ E. coli O7:K1 bacteria and thentreated with (1) vehicle, (2) 50 μg rBPI₂₁ only, (3) 20 mg/kgcefamandole only, or (4) both 50 μg rBPI₂₁ and 20 mg/kg cefamandole.Survival of the mice was followed over a period of 7 days; results oftwo trials are displayed in FIGS. 5A and 5B.

In one trial, rBPI₂₁ alone protected 11% of the survivors compared tovehicle controls. cefamandole protected 47 % of the survivors comparedto vehicle controls (p<0.05 vs. vehicle), and the concurrentadministration of rBPI₂₁ and cefamandole protected 100% of the survivorscompared to vehicle controls (p<0.00 1 vs. vehicle, p<0.01 vs.cefamandole alone). In the second trial, rBPI₂₁ alone protected 0% ofthe survivors compared to vehicle, cefamandole protected 12% compared tovehicle, and the concurrent administration of rBPI₂₁ and cefamandoleprotected 59% compared to vehicle (p<0.01 vs. vehicle, p<0.05 vs.cefamandole alone). In both trials, the increase in survival associatedwith the concurrent administration of rBPI₂₁ and cefamandole was greaterthan the sum of the increases in survival due to the individualtherapies. Thus, there appears to be synergy (a greater than additiveeffect) between cefamandole and BPI protein product in this model.

EXAMPLE 8 SYNERGISTIC EFFECTS OF CEFAMANDOLE AND BPI PROTEIN PRODUCT INVIVO IN RABBITS CHALLENGED INTRAVENOUSLY WITH LIVE E. COLI O7:K1BACTERIA: EFFECT ON BACTERIAL CLEARANCE AND ON CARDIOVASCULAR,RESPIRATORY AND METABOLIC PARAMETERS

Adult male New Zealand White rabbits (Charles River Laboratories, St.Constant, Canada) weighing between 1.8 and 2.3 kilograms were fasted for24 hours before the experiment. Each rabbit was anesthetized with anintramuscular injection of 80/4 mg/kg Ketamine/xylazine. The leftfemoral artery was catheterized for blood pressure determinations andblood sample collection. A catheter was placed adjacent the right atriumvia the right jugular vein and a thermistor-tipped catheter was placedin the aortic arch via the right carotid artery. The rabbits wereallowed to stabilize for 90-120 minutes following catheterization tonormalize hemodynamic and blood gas parameters.

The rabbits were divided into four treatment groups with 4 animals pergroup: (1) vehicle alone, (2) cefamandole and vehicle, (3) rBPI₂₁ andvehicle, and (4) cefamandole and rBPI₂₁. The rabbits were administeredcefamandole (Mandol®; Eli Lilly, Indianapolis, Ind.) or vehicleintravenously 5 minutes before the start of the bacterial infusion(considered to be T=0). At T=0, 2×10¹⁰ CFU/rabbit of E. coli O7:K1 wasinfused intravenously over 10 minutes into the ear vein. Simultaneously(at T=0), 10 mg/kg rBPI₂₁ or vehicle was infused over 10 minutes via theright jugular catheter. After the ten minute infusion, rBPI₂₁ was slowlyinfused at 10 mg/kg/hr for 2 hours (resulting in a total dose of 30mg/kg rBPI₂₁).

Arterial blood samples for determination of bacterial counts andendotoxin levels were collected at the end of the 10 minute bacterialinfusion and at 30 minutes, 1, 2, 3 and 4 hours. The whole blood was10-fold serially diluted in sterile PBS and aliquots were plated ontotryptic soy agar plates, incubated at 37° C. overnight, and the plateswere counted for colony forming units (CFU). The results were expressedas CFU/ml blood and percent bacteria dose per ml blood. The remainingportion of the blood was centrifuged, the plasma removed and passedthrough a 0.2 micron Whatman syringe filter to remove the bacteria. Theendotoxin levels were determined using a modified limulus amoebocytelysate assay (Pyrochrome LAL Assay, Associates of Cape Cod, Woods Hole,Mass.). These results were expressed as ng LPS per ml plasma.

Cardiovascular, respiratory and metabolic parameters were measured every30 minutes. Mean arterial blood pressure (MABP) and heart rate weremonitored continuously throughout the experiments and displayed on acardiac output computer (Columbus Instruments Cardiomax II) or on achart recorder. Heart rate was derived from the arterial pressure wave.Cardiac output was determined in duplicate with the thermodilutiontechnique: Changes in blood temperature resulting from injection of 900μl of room temperature PBS were recorded with the thermistor-tippedcatheter in the aortic arch. The cardiac output computer then generatedthermodilution curves that were visualized on the chart recorder, andderived cardiac output from the temperature-time curves. Cardiac index(CI) was then calculated as cardiac output per kg body weight. Inaddition, total peripheral resistance (TPR) was determined by dividingblood pressure by cardiac output.

Blood samples for blood gas determinations were drawn from the femoralartery catheter every 30 minutes throughout the study. Blood gases weremeasured with a Ciba-Coming Blood Gas System, Model 278 (Ciba-CorningDiagnostics Corp., Medfield, Mass.). The blood gas system directlymeasures blood pH, partial pressure of pCO₂, and partial pressure ofpO₂. Other parameters including the alveolar-arterial oxygen gradient,arterial oxygen content, estimated oxygen saturation, standardbicarbonate, and in vivo base excess were calculated using the formulasprovided by Ciba-Coming Diagnostic Corp. Plasma levels of glucose andlactate were determined using a Glucose/L-lactate Analyzer (2300 STAT,YSI, Yellow Springs, Ohio).

Survival data is shown in FIG. 6. Two of the four animals (50%) treatedwith vehicle alone died before the end of the experiment. None of theanimals concurrently treated with rBPI₂₁ and cefamandole died. Bacterialcounts in blood, expressed as CFU/ml or percent bacteria dose/ml, areshown in FIGS. 7 and 8, respectively. In FIG. 7, the squares representtreatment with vehicle alone, the diamonds represent cefamandole alone,the circles represent rBPI₂₁ alone, and the triangles represent theconcurrent administration of rBPI₂₁ and cefamandole. In FIG. 8, the barwith horizontal hatching indicates treatment with cefamandole alone, thehollow bar indicates the concurrent administration of rBPI₂₁ andcefamandole, the bar with vertical hatching indicates rBPI₂₁ alone, andthe solid bar indicates buffer alone. The group concurrently treatedwith rBPI₂₁ and cefamandole demonstrated a higher clearance of bacteriacompared to the groups treated with either rBPI₂₁ alone or cefamandolealone. There appears to be a synergistic effect at 30 and 60 minutes; at30 minutes, the concurrent administration of rBPI₂₁ and cefamandoleresulted in a higher percentage clearance of bacteria than the sum ofthe separate treatments.

Endotoxin levels are displayed in FIG. 9. The open diamonds indicatetreatment with vehicle alone, filled diamonds indicate rBPI₂₁ alone, thefilled squares indicate cefamandole alone, and the open squares indicateconcurrent administration of rBPI₂₁ and cefamandole. Animalsadministered cefamandole alone have a much higher LPS level than animalstreated with vehicle alone, due to release of LPS as cefamandole killsbacteria. The concurrent administration of rBPI₂₁ and cefamandoleproduced a dramatic decrease in LPS levels compared to cefamandoletherapy alone.

Cardiovascular/pulmonary parameters (MABP, CI, TPR, arterial oxygentension. alveolar-arterial O₂ gradient, respiration rate, and arterialblood pH) are shown in FIGS. 10-16, respectively. These figures onlydisplay results for the groups treated with cefamandole alone (indicatedby open squares) and concurrent treatment with rBPI₂₁ and cefamandole(indicated by filled squares). Single stars indicate that the concurrentadministration of both agents provided statistically significant(p<0.05) improvement over antibiotic alone, while two stars indicatep<0.01. Cefamandole alone or rBPI₂₁ alone failed to protect the animals;cardiovascular and respiratory dysfunction began du-ring the bacterialinfusion and the animals were in circulatory shock by the end of theinfusion. Cardiovascular shock lasted for the rest of the experiment.Arterial blood pH began to decrease at 60 minutes in the group treatedwith cefamandole alone, and was at its lowest level by the end of theexperiment. In contrast, concurrent administration of rBPI₂₁ andcefamandole preserved cardiopulmonary function and prevented septicshock. Thus, the concurrent administration of BPI protein product withantibiotic protected the animals against the lethal effect of bacteremiaand preserved cardiopulmonary function when antibiotic alone failed todo so.

EXAMPLE 9 SYNERGISTIC EFFECTS OF GENTAMICIN AND BPI PROTEIN PRODUCT INVIVO IN MICE CHALLENGED INTRAPERITONEALLY WITH LIVE E. COLI O7:K1BACTERIA: EFFECT ON SURVIVAL

The synergistic effects of an aminoglycoside antibiotic and a BPIprotein product were evaluated in mice challenged intraperitoneally withE. coli O7:K1 (ATCC Accession No. 23503), a smooth encapsulated strainthat is susceptible to the bactericidal effects of BPI protein product.The general procedure described above in Example 4 was followed. Sixgroups of 20 mice were challenged intraperitoneally with 2×10⁷ E. coliO7:K1 bacteria and treated immediately with (1) vehicle, (2) 0.03 mg/kggentamicin, (3) 0.1 mg/kg of gentamicin, (4) 50 μg of rBPI₂₁, (5) 0.03mg/kg gentamicin followed by 50 μg of rBPI₂₁, or (6) 0.1 mg/kg ofgentamicin followed by 50 μg of rBPI₂₁. Survival was followed over 7days. Results are shown in FIG. 17. Neither antibiotic alone nor rBPI₂₁alone had any effect on mortality other than to slightly retard thedeath rate. However, the concurrent administration of rBPI₂₁ withlow-dose gentamicin significantly increased survival (p<0.5 vs.vehicle). Concurrent administration of rBPI₂₁ with high-dose gentamicindramatically increased survival (p<0.001 vs. vehicle, and p<0.05 vs.0.03 mg/kg gentamicin with rBPI₂₁) protecting all but two of the micefrom the lethal effects of bacterial challenge. The results clearlyindicate synergism between gentamicin and BPI protein product. Thegreater synergistic effect of the concurrent administration of BPIprotein product with gentamicin, compared to the effect of theconcurrent administration of BPI protein product with cefamandole, maybe related to the fact that aminoglycosides, which inhibit proteinsynthesis, have a different mechanism of action than BPI proteinproduct.

EXAMPLE 10 EFFECT OF BPI PROTEIN PRODUCT IN VITRO ON ANTIBIOTICSUSCEFHBILITY OF CEFTRIAXONE-RESISTANT GRAM-NEGATIVE ORGANISMS

The ability of BPI protein product, BPI₂₁, to reverse the resistance ofa variety of gram-negative organisms to ceftriaxone (Roche Laboratories)was evaluated in vitro.

The strain of gram-negative bacteria to be tested was grown overnight at37° C. on Trypticase soy agar (TSA) plates. Colonies from the plate werethen inoculated into nutrient broth (or triethanolamine-buffered minimalsalts medium), grown overnight to stationary growth phase, diluted 1:10in fresh medium, and grown to mid-late logarithmic growth phase (3 to 4hours at 3° C.) to an approximate concentration of 6 to 10×10⁸organisms/mL. Organism counts were performed by making serial dilutions,plating in triplicate on TSA plates, incubating at 37° C. oventight, andcounting colonies by visual inspection. Following development of astandard curve, counts were made by measuring OD₅₄₀ and confirming byplating. The bacteria were sedimented by centrifugation at 6,000 g for10 min. and resuspended in sterile saline to the desired concentration.

Ceftriaxone solutions were prepared from standard powder (RocheLaboratories). Solutions of BPI protein product were prepared fromrBPI₂₁, Hanks solution, vitamin-free casamino acid, and TRIS-HCl buffer,pH 7.0. Broth MIC studies were performed as follows: U-bottom,disposable, microtiter array plates (Dynatech) containing 100 μL/well ofbroth and serial dilutions of 1:1 proportion rBPI₂₁ and ceftriaxone wereprepared using a multichannel pipetting instrument, inoculated withorganisms diluted to approximately 2.5×10⁵ CFU/ml, and incubatedovernight at 37° C. Media controls containing no organism and growthcontrols containing organisms but no ceftriaxone or rBPI₂₁ were alsoprepared. The MIC was determined as the lowest drag concentration(μg/mL) that inhibited bacterial growth. Agar MIC studies were performedas follows: The organism was grown in Mueller-Hinton broth (DifcoLaboratories) overnight at 37° C., transferred and grown to logarithmicphase, counted by optical densitometry, diluted with buffer and rBPI₂₁and ceftriaxone, and incubated for 30 minutes at 37° C. After the 30minutes of incubation, samples were serially diluted in sterile salineand plated onto TSA agar for bacterial counts after overnight incubationat 37° C.

A variety of different bacterial species were tested, includingPseudomonas, Enterobacter, Citrobacter, Klebsiella, and Escherichiaspecies. A summary of the results is displayed in Table 11 below, whichreports the minimum inhibitory concentration (MIC) of BPI proteinproduct alone, the MIC of ceftriaxone alone, and the MIC of both agentstogether (in a fixed 1:1 proportion of rBPI₂₁ and ceftriaxone). Theexperiments were replicated, and each number given in the tablerepresents the highest, or worst-case, MIC for the group.

                  TABLE 11                                                        ______________________________________                                        Synergistic Effect of rBPI.sub.21 and Ceftriaxone                             on Ceftriaxone-Resistant Organisms                                                    MIC of    MIC of       MIC of                                                 BPI alone Ceftriaxone alone                                                                          BPI + Ceftriaxone                              Organism                                                                              (μg/mL)                                                                              (μg/mL)   (μg/mL)                                     ______________________________________                                        PA 589  64        >64          4                                              PA 631  >64       >64          4                                              PA 672  32        32           2                                              PA 677  >64       >64          4                                              EA 658  >64       >64          4                                              CF 595  4         >64          1                                              CF 596  4         >64          1                                              CF 597  >64       >64          8                                              CF 598  8         32           2                                              CF 642  4         16           8                                              CF 661  32        16           1                                              KP 601  64        >64          8                                              EC 004  >64       >64          <0.1                                           EC 600  >64       32           8                                              EC 664  64        >64          32                                             ECL 03  16        >64          16                                             ECL 05  16        >64          16                                             ECL 07  >64       64           16                                             ECL 13  >64       >64          16                                             ECL 14  16        >64          32                                             ECL 15  >64       >64          32                                             ECL 19  >64       >64          32                                             PA 001  >64       >64          8                                              PA 003  >64       >64          8                                              PA 004  >64       64           16                                             PA 005  >64       >64          64                                             PA 012  >64       >64          16                                             PA 014  >64       >64          8                                              PA 017  >64       >64          32                                             PA 023  >64       >64          32                                             PA 026  64        64           8                                              PA 027  64        64           8                                              PA 028  >64       >64          16                                             ______________________________________                                         PA = Pseudomonas aeruginosa                                                   EA = Enterobacter aerogenes                                                   CF = Citrobacter freundii                                                     KP = Klebsiella pneumoniae                                                    EC = Escherichia coli                                                         ECL = Enterobacter cloacae                                               

Checkerboard synergy studies on selected strains were performed asfollows. Microplates were prepared using the foBowing organization:Column 1, control organisms (growth control); Columns 2 through 9,serial dilutions of cefiriaxone; Column 10, cefiriaxone alone; Column11, rBPI₂₁ alone; Column 12, control media; Rows 1 through 8, serialdilutions of rBPI₂₁. Columns 2 through 9 thus contained a serial arrayof various proportions of ceftriaxone and BPI concentrations. All webs,except the media control, were inoculated with suspended organisms andincubated oventight at 37° C. Turbidity was recorded at 24 and 48 hours.

Results of a representative synergy study of the effects of theconcurrent administration of rBPI₂₁ and cefiriaxone oncefiriaxone-resistant E. coli are shown in the checkerboard in Table 12below. In this checkerboard assay, rBPI₂₁ and cefiriaxone were eachserially diluted to concentrations ranging from 100 μg/ml to 0.8 μg/ml.These results show that the concurrent administration of both agents issynergistic. There was uniform growth in all growth control wells(containing bacteria, no rBPI₂₁ and no antibiotic), while there was nogrowth in the media control wells (containing no bacteria). There wasuniform growth in all ceftriaxone control webs (bacteria withceftriaxone alone). In the BPI control wells (bacteria with rBPI₂₁alone) there was growth in the wells with a concentration of 6.2 μg/mlrBPI₂₁ or less, and no growth at higher concentrations of BPI proteinproduct.

Survival (or kill) curve studies were performed as follows. Tubescontaining (1) media alone, (2) media plus ceftriaxone, (3) media plusrBPI₂₁, and (4) media plus cefiriaxone and rBPI₂₁, were prepared,inoculated with the desired organism, and incubated as described above.At 0, 1, 2, 4, 8 and 24 hours, diluted aliquots from each tube wereplated, incubated and counted as described above. Growth curves over 24hours (plots of log₁₀ CFU/mL versus time) were constructed todemonstrate the dynamics of antibiotic-BPI protein product interactionson bacterial growth and survival.

Results of a representative killing curve study of the effects of theconcurrent administration of rBPI₂₁ and ceftriaxone onceftriaxone-resistant E. coli are shown in FIG. 18. The filled square isthe control (neither rBPI₂₁ nor cefiriaxone), the open square is rBPI₂₁alone, the fried diamond is cefiriaxone alone, and the open diamond isthe concurrent administration of cefiriaxone and rBPI₂₁. Cefiriaxone orrBPI₂₁ alone have some early bactericidal effect at 4-8 hours, butorganism growth for both almost reaches that of the control curve by 24hours (about a 1 log difference from control). In contrast, theconcurrent administration of rBPI₂₁ and cefiriaxone produces asignificantly greater bactericidal effect that is sustained at 24 hours(a more than 6 log difference from control).

                                      TABLE 12                                    __________________________________________________________________________    Checkerboard Synergy Study for Ceftriaxone-Resistant E. coli Using            Ceftriaxone and rBPI.sub.21                                                             0.8 μg/mL                                                                         1.5 μg/mL                                                                        3.1 μg/mL                                                                         6.2 μg/mL                                                                        12.5 μg/mL                                                                        25 μg/mL                                                                         50 μg/mL                                                                          100 μg/mL                    Ceftriaxone                                                                          Ceftriaxone                                                                         Ceftriaxone                                                                          Ceftriaxone                                                                         Ceftriaxone                                                                          Ceftriaxone                                                                         Ceftriaxone                                                                          Ceftriaxone           __________________________________________________________________________    0.8                                                                              μg/mL BPI                                                                         +      +     0      0     0      0     0      0                     1.5                                                                              μg/mL BPI                                                                         +      0     0      0     0      0     0      0                     3.1                                                                              μg/mL BPI                                                                         0      0     0      0     0      0     0      0                     6.2                                                                              μg/mL BPI                                                                         0      0     0      0     0      0     0      0                     12.5                                                                             μg/mL BPI                                                                         0      0     0      0     0      0     0      0                     25 μg/mL BPI                                                                         0      0     0      0     0      0     0      0                     50 μg/mL BPI                                                                         0      0     0      0     0      0     0      0                     100                                                                              μg/mL BPI                                                                         0      0     0      0     0      0     0      0                     __________________________________________________________________________     KEY:                                                                          + Growth                                                                      0  No Growth                                                             

EXAMPLE 11 EFFECTS OF BPI PROTEIN PRODUCT AND ANTIBIOTICS IN VITRO ONPSEUDOMONAS SPECIES

The effects of a BPI protein product, rBPI₂₁, on the antibioticsusceptibility of clinical isolates of Pseudornonas aeruginosa and otherPseudornonas species (from Baxter Microscan® library, Sacramento,Calif.) was evaluated using Microscan® panel plates (Baxter Diagnostics,Inc., Deerfield, Ill.) that allow simultaneous determination of minimuminhibitory concentrations for a number of different antibiotics. Controlassays confirmed that the formulation buffer for rBPI₂₁ had no effect onthe antibiotic susceptibility of various organisms.

The antimicrobial susceptibility tests performed on the Microscan® panelplates are miniaturizations of the broth dilution susceptibility test.Antimicrobial agents are serially diluted in Mueller-Hinton broth(supplemented with calcium and magnesium, or with sodium chloride foroxacillin, or with thymidine phosphorylase for trimethoprim,sulfamethoxazole and trimethoprim/sulfamethoxazole) to concentrationsbridging the range of clinical interest. One well on the 96-wellMicroscan® plate is a growth control well that contains dehydrated brothonly. The remaining wells contain dehydrated broth and antibiotic (orbroth and biochemical reagent indicator), which is rehydrated to thedesired concentration by inoculation of a standardized suspension oftest organism. The chromogenic biochemical agent indicators are used toidentify and characterize the species of bacteria based on detection ofpH changes and substrate utilization. After incubation overnight, theminimum inhibitory concentration (MIC) of an antibiotic for the testorganism is determined by observing the well with the lowestconcentration of the antibiotic that shows inhibition of growth.Gram-negative organisms were tested using Neg Combo Type 16, MIC PlusType 2, or Neg Breakpoint Combo Type 9 panel plates (Microscan®, BaxterDiagnostics, Inc., Deerfield, Ill.). The concentrations of antibioticstested in these panel plates are shown below in Tables 13, 14 and 15,respectively. The antibiotic susceptibility standards (interpretation ofan MIC as resistant, intermediate or susceptible according toMicroscan®'s NCCLS-derived standards) applicable to the gram-negativeorganisms tested in each panel plate appear in Tables 13A, 14A and 15A,respectively.

                  TABLE 13                                                        ______________________________________                                        ANTIBIOTIC CONCENTRATIONS TESTED IN                                           NEG COMBO TYPE 16 PANEL PLATE                                                                     Two-Fold Serial                                           Antibiotic          Dilutions Tested μg/ml                                 ______________________________________                                        Amikacin            2-16                                                      Ampicillin          2-16                                                      Ampicillin/Sulbactam                                                                              8/4-16/8                                                  Aztreonam           8-16                                                      Cefazolin           2-16                                                      Cefotaxime          4-32                                                      Cefoxitin           2-16                                                      Ceftazidime         2-16                                                      Ceftriaxone         4-32                                                      Cefuroxime          2-16                                                      Ciprofloxacin       1-2                                                       Gentamicin           1-4,6                                                    Imipenem            4-8                                                       Ofloxacin           2-4                                                       Piperacillin        8-64                                                      Ticarcillin         8-64                                                      Tobramycin           1-4,6                                                    Trimethoprim/Sulfamethoxazole                                                                     0.5/9.5, 2/38                                             ______________________________________                                    

                  TABLE 13A                                                       ______________________________________                                        MICROSCAN NEG COMBO PANEL 16                                                  ANTIBIOTIC SUSCEPTIBILITY RANGES                                              FOR GRAM-NEGATIVE BACTERIA                                                                 MIC (μg/ml)                                                   Antibiotic     Resistant                                                                              Intermediate                                                                             Susceptible                                ______________________________________                                        Amikacin       >16                 ≦16                                 Ampicillin.sup.E                                                                             >16      16         ≦8                                  Ampicillin/Sulbactam.sup.E                                                                   >16/8     16/8      ≦8/4                                Aztreonam      >16      16         ≦8                                  Cefazolin      >16      16         ≦8                                  Cefotaxime     >32      16-32      ≦8                                  Cefoxitin      >16      16         ≦8                                  Ceftazidime    >16      16         ≦8                                  Ceftriaxone    >32      16-32      ≦8                                  Cefuroxime     >16      16         ≦8                                  Ciprofloxacin  >2        2         ≦1                                  Gentamicin     >6        6         ≦4                                  Imipenem       >8        8         ≦4                                  Ofloxacin      >4        4         ≦2                                  Piperacillin.sup.E                                                                           >64      32-64      ≦16                                 Piperacillin.sup.P                                                                           >64                 ≦64                                 Ticarcillin.sup.E                                                                            >64      32-64      ≦16                                 Ticarcillin.sup.P                                                                            >64                 ≦64                                 Tobramycin     >6        6         ≦4                                  Trimethoprim/Sulfameth-                                                                      >2/38               ≦2/38                               oxazole                                                                       ______________________________________                                         .sup.E Enterobacteriaceae only                                                .sup.P Pseudomonas only                                                  

                  TABLE 14                                                        ______________________________________                                        ANTIBIOTIC CONCENTRATIONS TESTED IN                                           MIC PLUS TYPE 2 PANEL PLATE                                                                     Two-Fold Serial                                             Antibiotic        Dilutions Tested (μg/ml)                                 ______________________________________                                        Amoxicillin/K Clavulanate                                                                       1/0.5-32/16                                                 Ampicillin/Sulbactam                                                                            1/0.5-32/16                                                 Azlocillin        64                                                          Azetreonam        1-32                                                        Carbenicillin     16-128                                                      Cefamandole       4-32                                                        Cefonicid         2-16                                                        Cefoperazone      4-32                                                        Cefotaxime        2-64                                                        Cefotetan         4-32                                                        Ceftazidime       1-32                                                        Ceftizoxime       2-32                                                        Ceftriaxone       2-64                                                        Chloramphenicol   2-16                                                        Ciprofloxacin     0.25-4                                                      Imipenem          0.5-16                                                      Mezlocillin       16-128                                                      Netilmicin        2-16                                                        Ticarcillin       16-128                                                      Ticarcillin/K Clavulanate                                                                       16-128                                                      ______________________________________                                    

                  TABLE 14A                                                       ______________________________________                                        MICROSCAN MIC PLUS TYPE 2 ANTIBIOTIC                                          SUSCEPTIBILITY RANGES FOR                                                     GRAM-NEGATIVE BACTERIA                                                                   MIC (μg/ml)                                                     Antibiotic   Resistant Intermediate                                                                             Susceptible                                 ______________________________________                                        Amoxicillin/K-                                                                             ≧32/16                                                                            16/8      ≦8/4                                 Clavulanate                                                                   Ampicillin/Sulbactam                                                                       ≧32/16                                                                            16/8      ≦8/4                                 Azlocillin.sup.P                                                                           >64                  ≦64                                  Aztreonam    ≧32                                                                              16         ≦8                                   Carbenicillin.sup.E                                                                        ≧64                                                                              32         ≦16                                  Carbenicillin.sup.P                                                                        >128                 ≦128                                 Cefamandole  ≧32                                                                              16         ≦8                                   Cefonicid    >16       16         ≦8                                   Cefoperazone >32       32         ≦16                                  Cefotaxime   ≧64                                                                              16-32      ≦8                                   Cefotetan    >32       32         ≦16                                  Ceftazidime  ≧32                                                                              16         ≦8                                   Ceftizoxime  >32       16-32      ≦8                                   Ceftriaxone  ≧64                                                                              16-32      ≦8                                   Chloramphenicol                                                                            >16       16         ≦8                                   Ciprofloxacin                                                                               ≧4                                                                               2         ≦1                                   Imipenem     ≧16                                                                               8         ≦4                                   Mezlocillin.sup.E                                                                          ≧128                                                                             32-64      ≦16                                  Mezlocillin.sup.P                                                                          ≧128          ≦64                                  Netilmicin   >16       16         ≦8                                   Ticarcillin.sup.E                                                                          ≧128                                                                             32-64      ≦16                                  Ticarcillin.sup.P                                                                          ≧128          ≦64                                  Ticarcillin/K-                                                                             ≧128                                                                             32-64      ≦16                                  Clavulanate.sup.E                                                             Ticarcillin/K-                                                                             ≧128          ≦64                                  Clavulanate.sup.P                                                             ______________________________________                                         Enterobacteriaceae only                                                       Pseudomonas only                                                         

                  TABLE 15                                                        ______________________________________                                        ANTIBIOTIC CONCENTRATIONS TESTED IN                                           NEG BREAKPOINT COMBO TYPE 9 PANEL PLATE                                       Antibiotic         Dilutions Tested (μg/ml)                                ______________________________________                                        Nitrofurantoin     32 & 64                                                    Cephalothin         8 & 16                                                    Ampicillin          8 & 16                                                    Oftoxacin          2 & 4                                                      Ticarcillin        16 & 64                                                    Piperacillin       16 & 64                                                    Mezlocillin        16 & 64                                                    Tetracycline       4 & 8                                                      Ampicillin/Sulbactam                                                                              8/4 & 16/8                                                Amoxicillin/K Clavulanate                                                                         8/4 & 16/8                                                Ticarcillin/K Clavulanate                                                                        16 & 64                                                    Gentamicin         4 & 8                                                      Tobramycin         4 & 8                                                      Amikacin           16 & 32                                                    Ciprofloxacin      1 & 2                                                      Imipenem           4 & 8                                                      Cefazolin           8 & 16                                                    Cefamandole         8 & 16                                                    Cefuroxime          8 & 16                                                    Cefotetan          16 & 32                                                    Cefoxitin           8 & 16                                                    Aztreonam           8 & 16                                                    Ceftriaxone         8 & 32                                                    Ceftazidime         8 & 16                                                    Cefoperazone       16 & 32                                                    Cefotaxime          8 & 32                                                    Chloramphenicol     8 & 16                                                    Trimethoprim/Sulfamethoxazole                                                                     2/38 & 8/152                                              Norfloxacin        4 & 8                                                      Cinoxacin          16                                                         Trimethoprim        8                                                         Sulfamethoxazole   256                                                        ______________________________________                                    

                  TABLE 15A                                                       ______________________________________                                        MICROSCAN NEG BREAKPOINT COMBO TYPE 9                                         ANTIBIOTIC SUSCEPTIBILITY RANGES                                              FOR GRAM-NEGATIVE BACTERIA                                                                 MIC (μg/ml)                                                   Antibiotic     Resistant                                                                              Intermediate                                                                             Susceptible                                ______________________________________                                        Nitrofurantoin >64      64         ≦32                                 Cephalothin    >16      16         ≦8                                  Ampicillin.sup.E                                                                             >16      16         ≦8                                  Ofloxacin      >4        4         ≦2                                  Ticarcillin.sup.E                                                                            >64      64         ≦16                                 Ticarcillin.sup.P                                                                            >64                 ≦64                                 Piperacillin.sup.E                                                                           >64      64         ≦16                                 Piperacillin.sup.P                                                                           >64                 ≦64                                 Mezlocillin.sup.E                                                                            >64      64         16                                         Mezlocillin.sup.P                                                                            >64                 ≦64                                 Tetracycline   >8        8         ≦4                                  Ampicillin/Sulbactam.sup.E                                                                   >16/8     16/8      ≦8/4                                Amoxicillin/K- >16/8     16/8      ≦8/4                                Clavulanate    >16/8     16/8      ≦8/4                                Ticarcillin/K- >64      64         ≦16                                 Clavulanate.sup.E                                                             Ticarcillin/K- >64                 ≦64                                 Clavulanate.sup.P                                                             Gentamicin     >8        8         ≦4                                  Tobramycin     >8        8         ≦4                                  Amikacin       >32      32         ≦16                                 Ciprofloxacin  >2        2         ≦1                                  Imipenem       >8        8         ≦4                                  Cefazolin      >16      16         ≦8                                  Cefamandole    >16      16         ≦8                                  Cefuroxime     >16      16         ≦8                                  Cefotetan      >32      32         ≦16                                 Cefoxitin      >16      16         ≦8                                  Aztreonam      >16      16         ≦8                                  Ceftriaxone    >32      32         ≦8                                  Ceftazidime    >16      16         ≦8                                  Cefoperazone   >32      32         ≦16                                 Cefotaxime     >32      32         ≦8                                  Chloramphenicol                                                                              >16      16         ≦8                                  Trimethoprim/Sulfameth-                                                                      >8/152     8/152    ≦2/38                               oxazole                                                                       Norfloxacin    >8        8         ≦4                                  Cinoxacin      >16                 ≦16                                 Trimethoprim   >8                  ≦8                                  Sulfamethoxazole                                                                             >256                ≦256                                ______________________________________                                         .sup.E Enterobacteriacaeae only                                               .sup.P Pseudomonas only                                                  

For each experimental run, the following procedure was performed: Theorganism was streaked onto 5% sheep blood agar plates (Remel, Lenexa,Kansas) and incubated for 18-24 hours overnight. Well-isolated coloniesfrom the plates were emulsified in 3 ml of sterile Inoculum Water(catalog no. B1015-2, MicroScan® system, Baxter Diagnostics, Inc.,Deerfield, Ill.) to a final turbidity equivalent to 0.5 McFarland BariumSulfate standard. This cell suspension was vortexed for 2 to 3 secondsand 100 μl was transferred to glass tubes containing 25 ml of InoculumWater with Pluronic-D (catalog no. B1015-7, MicroScan® system, BaxterDiagnostics, Inc., Deerfield, Ill.) (hereinafter "Pluronic InoculumWater"), or 25 ml of Pluronic Inoculum Water into which rBPI₂₁ (informulation buffer) had been diluted to the desired concentrationbetween 0.5 to 64 μg/ml rBPI₂₁.

The 25 ml of this inoculum containing rBPI₂₁ was mixed by inversion andpoured into a tray. The inoculum was drawn up into a manual 96-wellpipetting system (RENOK™ rehydrator-inoculator system, Baxter HealthCare Corporation, West Sacramento, Calif.) designed for use with theMicroscan® panel plates, and 110 μl of the inoculum was delivered toeach well of a Microscan® Neg Combo Type 16 panel plate. When added tothe wells, this inoculum achieves a final bacterial concentration of4×10⁵ to 7×10⁵ CFU/ml. The panel plates were then incubated at 35° C.for 15-24 hours and read visually for cell growth.

No growth was defined as a slight whiteness in the well or a clearbroth. Growth appeared as turbidity which could take the form of a whitehaze throughout the well, a white button in the center of the well, or afine granule growth throughout the well. All wells were read against ablack indirectly lighted background. Visual results of the biochemicalreactions were read into a database for bacterial identification. TheMICs for each antibiotic tested were determined by identifying thelowest concentration of antibiotic which inhibited visible growth.

The clinical isolates of Pseudomonas aeruginosa and other Pseudomonasspecies were tested using the Neg Combo Type 16 panel plate. Tables 16,17 and 18 below display a summary of the results of the antibioticscreening panels, reported for each strain tested as the MIC of thetested antibiotics at the various concentrations of rBPI₂₁ indicated.Results are reported for each strain tested, but susceptibility data islisted for only those antibiotics for which BPI protein product alteredsusceptibility. The antibiotic susceptibility standards (interpretationof an MIC as resistant, intermediate or susceptible according toMicroscan®'s NCCLS-derived standards) applicable to the organism testedappear in Table 13A. Stars after the antibiotic name in the "antibiotictested" column indicate whether rBPI₂₁ reversed the resistance of thatorganism to the antibiotic tested (two stars) or converted anindifferent MIC into a susceptible MIC (one star). These data show thatBPI protein product reversed resistance to ticarcillin, cefazolin,cefoxitin, cefuroxime, ofloxacin, aztreonam, piperacillin, and amikacinfor some strains of P. aeruginosa and increased the susceptibility ofsome P. aeruginosa strains to ticarcillin, aztreonam, imipenem,piperacillin, ofloxacin, ceftazidime, amikacin, ceftriaxone, cefotaxime,cefuroxime, tobramycin, ciprofloxacin, trimethoprim/sulfamethoxazole,gentamicin, and cefazolin. BPI protein product reversed resistance ofsome P. cepacia strains to cefazolin, cefoxitin, cefuroxime,ceftriaxone, ticarcillin, and increased the susceptibility of some P.cepacia strains to ampicillin, ticarcillin, piperacillin, cefazolin,cefoxitin, cefuroxime, ceftriaxone, ampicillin/sulbactam, cefotaxime,gentamicin, tobramycin, and amikacin. BPI protein product reversedresistance of Xanthamonas maltophilia to trimethoprim/sulfamethoxazole,piperacillin and amikacin, and increased susceptibility tociprofloxacin.

Tables 16, 17 and 18 also show the presence or absence of bacterialgrowth in the growth control wells, which contained varyingconcentrations of rBPI₂₁ alone without antibiotic. "G" indicates growth,while "NG" indicates no growth. These results indicate that rBPI₂₁ at aconcentration of 32 μg/ml has direct bactericidal/growth inhibitoryeffects on some of the tested Pseudomonas isolates.

                  TABLE 16                                                        ______________________________________                                        EFFECTS OF rBPI.sub.21 ± ANTIBIOTICS ON Pseudomonas                        aeruginosa                                                                                   Minimum                                                                       Inhibitory Concentration                                                      of Antibiotic (μg/mL)                                       Microscan            With     With   With                                     Library Antibiotic   0 μg/mL                                                                             8 μg/mL                                                                           32 μg/mL                              ID No.  Tested       rBPI.sup.21                                                                            rBPI.sup.21                                                                          rBPI.sub.21                              ______________________________________                                        19610   BPI          G        G      G                                                Ticarcillin**                                                                              >64        64     64                                             Aztreonam*     16      <8     <8                                              Piperacillin   332      16    <8                                              Ofloxacin**   >4         4    <2                                              Ceftazidime     8        8      4                                             Amikacin       16        8      8                                     18433   BPI          G        G      NG                                               Azetreonam*    16      <8    --                                               Ceftriaxone  >32        32   --                                               Cefotaxime   >32        32   --                                               Cefuroxime*    16        4   --                                               Tobramycin      2      <1    --                                               Amikacin       16         8  --                                       12892   BPI          G        G      G                                                Ciprofloxacin                                                                               >2       >2       2                                             Oflaxacin     >4      `>4       4                                             Ceftazidime     4        4    <2                                              Cefotaxime   >32      >32      32                                             Amikacin       16       16      8                                     19054   BPI          G        G      G                                                Trimethoprim/                                                                               >2       >2       2                                             Sulfamethoxazole                                                              Ticarcillin    64       16     16                                             Ceftriaxone*   16       32      8                                             Gentamicin      4        4      2                                             Amikacin       16        8      4                                             Cefazolin    >16      >16      16                                     19672   BPI          G        G      G                                                Tobramycin    >6       >6       6                                     19551   BPI          G        G      G                                                Aztreonam**  >16       <8     <8                                              Piperacillin**                                                                             >64       <8     <8                                              Ceftriaxone    32       16     16                                             Gentamicin      4      <1     <1                                              Tobramycin      2      <1     <1                                              Amikacin**   >16       <2     <2                                      19660   BPI          G        G      NG                                               Trimethoprim/                                                                               >2         2   --                                               Sulfamethoxazole                                                              Ceftriaxone*   16        8   --                                               Cefotaxime     16       16   --                                       Opal.sup.b                                                                            BPI          G        G      G                                                Ampicillin.sup.a                                                                           >16      >16       4                                             Trimethoprim/                                                                               >2       >2       2                                             Sulfamethoxazole                                                              Ticarcillin    16       16    <8                                              Cefazolin**  >16      >16     <2                                              Cefoxitin**  >16      >16     <2                                              Cefuroxime** >16      >16     <2                                              Ceftriaxone*   16        8    <4                                              Ampicillin/  >16      >16     <8                                              Sulbactam.sup.a                                                               Cefotaxime*    16        8    <4                                      ______________________________________                                         .sup.a The Microscan ® worksheet did not supply antibiotic                susceptibility ranges, but there was reversal of antibiotic indifference      according to NCCLS standards, Publication M7A3, Table 2 (1993).               .sup.b Strain 12.4.4, provided by S. M. Opal, Brown University,               Providence, RI.                                                          

                  TABLE 17                                                        ______________________________________                                        EFFECTS OF rBPI.sub.21 ± ANTIBIOTICS ON Pseudomonas                        aeruginosa                                                                                   Minimum                                                                       Inhibitory Concentration                                                      of Antibiotic (μg/mL)                                       Microscan            With     With   With                                     Library Antibiotic   0 μg/mL                                                                             4 μg/mL                                                                           16 μg/mL                              ID No.  Tested       rBPI.sup.21                                                                            rBPI.sub.21                                                                          rBPI.sub.21                              ______________________________________                                        N113-100                                                                              BPI          G        G      G                                                Ofloxacin*      4        4    <2                                              Gentamicin    >6         6      6                                             Tobramycin      2        2    <1                                      N113-101                                                                              BPI          G        G      G                                                Aztreonam    >16      >16     <8                                              Ofloxacin*      4        4    <2                                              Gentamicin    >6         6      6                                             Tobramycin      4        2    <1                                      N113-102                                                                              BPI          G        G      G                                                Piperacillin   64      <8     <8                                              Ceftriaxone*   32       16      8                                             Cefotaxime     32       16     16                                             Gentamicin      4        4    <1                                              Amikacin        8        8    <2                                      N113-103                                                                              BPI          G        G      G                                                Ticarcillin    16       16     32                                             Amikacin        4        8      4                                     N113-104                                                                              BPI          G        G      G                                                Ceftazidime   <2       <2       4                                             Ceftriaxone*   16        8      8                                     N113-105                                                                              BPI          G        G      G                                                Ticarcillin    64       32     32                                             Aztreonam*     16      <8     <8                                              Ceftriaxone    32       32     16                                             Cefotaxime     32       32     16                                             Gentamicin      2        2    <1                                      N113-106                                                                              BPI          G        G      G                                                Ticarcillin    16       16    <8                                              Ceftriaxone*   32       16      8                                             Cefotaxime*    16       16      8                                             Gentamicin      4        2       2                                            Amikacin        8        4      4                                     N113-107                                                                              BPI          G        G      G                                                Ticarcillin  >64      >64      64                                             Ciproflaxacin*                                                                                2        2    <1                                              Ceftazidime     8        4      4                                             Ceftriaxone    32       32   >32                                              Imipenem      >8         8    >8                                      ______________________________________                                    

                  TABLE 18                                                        ______________________________________                                        EFFECTS OF rBPI.sub.21 ± ANTIBIOTICS ON Pseudomonas                        SPECIES                                                                                      Minimum                                                                       Inhibitory Concentration                                                      of Antibiotic (μg/mL)                                       Microscan            With     With   With                                     Library Antibiotic   0 μg/mL                                                                             8 μg/mL                                                                           32 μg/mL                              ID No.  Tested       rBPI.sup.21                                                                            rBPI.sub.21                                                                          rBPI.sub.21                              ______________________________________                                        31142   BPI          G        G      G                                        ( P. cepacia)                                                                         Ampicillin   >16        16   --                                               Ticarcillin    32      <8    --                                               Piperacillin   32      <8    --                                               Cefazolin**  >16         8   --                                               Cefoxitin**  >16       <2    --                                               Cefuroxime** >16       <2    --                                               Ceftriaxone**                                                                              >32         8   --                                               Ampicillin/    16      <8    --                                               Sulbactam.sup.a                                                               Cefotaxime*    32      <4    --                                               Gentamicin*     6      <1    --                                               Tobramycin      2      <1    --                                               Amikacin        8      <2    --                                       12122   BPI          G        G      G                                        ( P. cepacia )                                                                        Ticarcillin**                                                                              >64        64     32                                             Piperacillin   16      <8     <8                                              Cefuroxime      4      <2     <2                                              Amikacin        4        4    <2                                      17211   BPI          G        G      NG                                       (Xantha-                                                                              Trimethoprim/                                                                               >2         2   --                                       monas   Sulfa-                                                                maltophilia)                                                                          methoxazole**                                                                 Piperacillin**                                                                             >64        16   --                                               Amikacin**   >16        16   --                                               Ciprofloxacin                                                                                 2        2   --                                       ______________________________________                                         .sup.a The Microscan ® worksheet did not supply antibiotic                susceptiblity ranges for this organism, but there was reversal of             antibiotic indifference according to NCCLS standards, Publication M7A3,       Table 2 (1993).                                                          

EXAMPLE 12 EFFECTS OF BPI PROTEIN PRODUCT AND ANTIBIOTICS IN VITRO ONSTRAINS OF E. COLI

The effect of a BPI protein product, rBPI₂₁, on the antibioticsusceptibility of various strains of E. coli was evaluated in theMicroscan® antibiotic susceptibility screening assay of Example 11 usingthe Neg Combo Type 16 panel plate. The direct growth inhibitory effectof rBPI₂₁ on these strains was also evaluated in the same assay. Assayswere conducted on clinical isolates of E. coli (from Baxter Microscan®library, Sacramento, Calif.).

A summary of the results of the antibiotic screening panels, reported asMICs (μg/ml) of the antibiotic tested, is shown in Table 19 below.Results are reported for each strain tested, but susceptibility data islisted for only those antibiotics for which BPI protein product alteredsusceptibility. The antibiotic susceptibility standards (interpretationof an MIC as resistant, intermediate or susceptible according toMicroscan®'s NCCLS-derived standards) applicable to the organism testedappear in Table 13A. These results show that BPI protein productreversed the resistance of some strains to cefazolin and increased thesusceptibility of other strains to ampicillin, cefuroxime, cefazolin,amikacin, and cefoxitin.

                  TABLE 19                                                        ______________________________________                                        EFFECTS OF rBPI.sub.21 ± ANTIBIOTICS ON Escherichia coli                                  Minimum                                                                       Inhibitory Concentration                                                      of Antibiotic (μg/mL)                                       Microscan            With     With   With                                     Library Antibiotic   0 μg/mL                                                                             4 μg/mL                                                                           16 μg/mL                              ID No.  Tested       rBPI.sup.21                                                                            rBPI.sub.21                                                                          rBPI.sub.21                              ______________________________________                                        19536   Ampicillin.sup.a                                                                           16       16     8                                                Cefuroxime   4        8      4                                        F101-309                                                                              Cefoxitin    4        <2     4                                                Cefuroxime   8        4      4                                        19612   Cefazolin**  >16      >16    8                                                Amikacin     16       8      8                                                Cefoxitin    <2       4      <2                                       17164   Ampicillin   8        8      4                                                Cefoxitin    8        8      4                                        19522   Cefazolin    8        8      4                                                Cefoxitin    >16      >16    16                                       ______________________________________                                         .sup.a The Microscan ® worksheet did not supply antibiotic                susceptibility ranges for this organism, but there was reversal of            antibiotic indifference according to NCCLS standards, Publication M7A3,       Table 2 (1993).                                                          

EXAMPLE 13 EFFECTS OF BPI PROTEIN PRODUCT AND ANTIBIOTICS IN VITRO ONCITROBACTER SPECIES

The effect of a BPI protein product, rBPI₂, on the antibioticsusceptibility of various Citrobacter species was evaluated in theMicroscan® antibiotic susceptibility screening assay of Example 11 usingthe Neg Combo Type 16 panel plate. The direct growth inhibitory effectof rBPI₂₁ on these strains was also evaluated in the same assay. Assayswere conducted on clinical isolates of Citrobacter species (from BaxterMicroscan® library, Sacramento, Calif.).

A summary of the results of the antibiotic screening panels, reported asMICs (μg/ml) of the antibiotic tested, is shown in Table 20 below.Results are reported for each strain tested, but susceptibility data islisted for only those antibiotics for which BPI protein product alteredsusceptibility. The antibiotic susceptibility standards (interpretationof an MIC as resistant, intermediate or susceptible according toMicroscan®'s NCCLS-derived standards) applicable to the organism testedappear in Table 13A. These results show that BPI protein productincreased the susceptibility of the tested Citrobacter species toaztreonam, cefotaxime, tobramycin, amikacin, cefuroxime, ampicillin,ticarcillin, pipemcillin, and cefuroxime.

                  TABLE 20                                                        ______________________________________                                        EFFECTS OF rBPI.sub.21 ± ANTIBIOTICS ON Citrobacter                        SPECIES                                                                                      Minimum                                                                       Inhibitory Concentration                                                      of Antibiotic (μg/mL)                                       Microscan            With     With   With                                     Library  Antibiotic  0 μg/mL                                                                             4 μg/mL                                                                           16 μg/mL                              ID No.   Tested      rBPI.sup.21                                                                            rBPI.sub.21                                                                          rBPI.sub.21                              ______________________________________                                        18419    Aztreonam   >16      >16     16                                      ( C. freundii)                                                                         Cefotaxime  >32        32    32                                               Tobramycin     4        2   <1                                                Amikacin       4      <2      4                                      18420    Cefuroxime  >16      >16     16                                      (C. freundii)                                                                          Amikacin     >2       >2    >2                                       F-052-007                                                                              Ampicillin  >16      >16     16                                      (C. diversus)                                                                          Ticarcillin >64      >64     64                                               Piperacillin.sup.a                                                                          32       16   <8                                                Cefuroxime     8        4     4                                      ______________________________________                                         .sup.a The Microscan ® worksheet did not supply antibiotic                susceptibility ranges for this organism, but there was reversal of            antibiotic indifference according to NCCLS standards, Publication M7A3,       Table 2 (1993).                                                          

EXAMPLE 14 EFFECTS OF BPI PROTEIN PRODUCT AND ANTIBIOTICS IN VITRO ONKLEBSIELLA SPECIES

The effect of a BPI protein product, rBPI₂₁, on the antibioticsusceptibility of various Klebsiella species was evaluated in theMicroscan® antibiotic susceptibility screening assay of Example 11 usingthe Neg Combo Type 16 panel plate. The direct growth inhibitory effectof rBPI₂₁ on these strains was also evaluated in the same assay. Assayswere conducted on clinical isolates of Klebsiella species (from BaxterMicroscan® library, Sacramento, Calif.).

A summary of the results of the antibiotic screening panels, reported asMICs (μg/ml) of the antibiotic tested, is shown in Table 21 below.Results are reported for each strain tested, but susceptibility data islisted for only those antibiotics for which BPI protein product alteredsusceptibility. The antibiotic susceptibility standards (interpretationof an MIC as resistant, intermediate or susceptible according toMicroscan®'s NCCLS-derived standards) applicable to the organism testedappear in Table 13A. These results show that BPI protein productreversed the resistance of one strain of K. pneumoniae totrimethoprim/suffamethoxazole and increased the susceptibility of thetested species to cefoxitin, ampicillin/sulbactam,trimethoprim/sulfamethoxazole, cefazolin, and cefuroxime.

                  TABLE 21                                                        ______________________________________                                        EFFECTS OF rBPI.sub.21 ± ANTIBIOTICS ON Klebsiella                         SPECIES                                                                                      Minimum                                                                       Inhibitory Concentration                                                      of Antibiotic (μg/mL)                                       Microscan            With     With   With                                     Library  Antibiotic  0 μg/mL                                                                             4 μg/mL                                                                           16 μg/mL                              ID No.   Tested      rBPI.sup.21                                                                            rBPI.sub.21                                                                          rBPI.sub.21                              ______________________________________                                        19645    Cefoxitin     8      <2       4                                      ( K.     Cefoxitin     8      <2       4                                      pneumoniae)                                                                            Ampicillin/ >16      >16    >16                                               Sulbactam                                                            18427    Cefazolin   <2         4    <2                                       (K.      Ampicillin/  16       16    <8                                       pneumoniae)                                                                            Sulbactam.sup.a                                                      16135    Trimethoprim/                                                                             >2       >2       <0.5                                   ( K.     Sulfa-                                                               pneumoniae)                                                                            methoxazole**                                                                 Cefazolin*   16       16      8                                      30434    Cefazolin*   16       16      8                                      (K. oxytoca)                                                                           Cefoxitin     4      <2       4                                               Cefuroxime    8        4      8                                               Ampicillin/ <8        16    <8                                                Sulbactam                                                            ______________________________________                                         .sup.a The Microscan ® worksheet did not supply antibiotic                susceptibility ranges for this organism, but there was reversal of            antibiotic indifference according to NCCls standards, Publication M7A3,       Table 2 (1993).                                                          

EXAMPLE 15 EFFECTS OF BPI PROTEIN PRODUCT AND ANTIBIOTICS IN VITRO ONENTEROBACTER SPECIES

The effect of a BPI protein product, rBPI₂₁, on the antibioticsusceptibility of various Enterobacter species was evaluated in theMicroscan® antibiotic susceptibility screening assay of Example 11 usingthe Neg Combo Type 16 panel plate. The direct growth inhibitory effectof rBPI₂₁ on these strains was also evaluated in the same assay. Assayswere conducted on clinical isolates of Enterobacter species (from BaxterMicroscan® library, Sacramento, Calif.).

A summary of the results of the antibiotic screening panels, reported asMICs (μg/ml) of the antibiotic tested, is shown in Table 22 below.Results are reported for each strain tested, but susceptibility data islisted for only those antibiotics for which BPI protein product alteredsusceptibility. The antibiotic susceptibility standards (interpretationof an MIC as resistant, intermediate or susceptible according toMicroscan®'s NCCLS-derived standards) applicable to the organism testedappear in Table 13A. These results show that BPI protein productreversed the resistance of one strain of E. cloacae to ticarcillin,cefuroxime, ceftazidime and cefotaxime. BPI protein product alsoincreased the susceptibility of some Enterobacter species toticarcillin, aztreonam, piperacillin, ciprofloxacin, cefotaxime,trimethoprim/sulfamethoxazole, cefuroxime, ceftazidime, ceftriaxone, andampicillin/sulbactam.

                  TABLE 22                                                        ______________________________________                                        EFFECTS OF rBPI.sub.21 ± ANTIBIOTICS ON Enterobacter                       SPECIES                                                                                      Minimum                                                                       Inhibitory Concentration                                                      of Antibiotic (μg/mL)                                       Microscan            With     With   With                                     Library  Antibiotic  0 μg/mL                                                                             4 μg/mL                                                                           16 μg/mL                              ID No.   Tested      rBPI.sup.21                                                                            rBPI.sub.21                                                                          rBPI.sub.21                              ______________________________________                                        19565    Ticarcillin   64     >64      64                                     ( E. aerogenes)                                                                        Aztreonam*    16      <8     <8                                               Piperacillin                                                                              >64      >64      64                                              Ciprofloxacin*                                                                               2      <1     <1                                               Cefotaxime*   16        8      8                                     19626    Piperacillin                                                                              >64        64     64                                     (E. aerogenes)                                                                         Ticarcillin >64      >64    >64                                      19625    Trimethoprim/                                                                                2     <0.5   <0.5                                     (E. aerogenes)                                                                         Sulfa-                                                                        methoxazole*                                                                  Piperacillin                                                                              >64      >64    >64                                      19680    Ticarcillin**                                                                             >64      >64     <8                                      (E. cloacae)                                                                           Aztrenam    >16        16    <8                                               Piperacillin*                                                                               64       32    <8                                               Cefuroxime**                                                                              >16      >16       8                                              Ceftazidime**                                                                             >32        32    <4                                               Ceftriaxone >16      >16      16                                              Ampicillin/ >16      >16      16                                              Sulbactam                                                                     Cefotaxime**                                                                              >32      >32     <4                                      19686    Ceftriaxone   32       32     16                                     (E. cloacae)                                                                           Piperacillin                                                                              >64      >64    >64                                      ______________________________________                                    

EXAMPLE 16 EFFECTS OF BPI PROTEIN PRODUCT AND ANTIBIOTICS IN VITRO ONSERRATIA MARCESCENS

The effect of a BPI protein product, rBPI₂₁, on the antibioticsusceptibility of Serratia marcescens was evaluated in the Microscan®antibiotic susceptibility screening assay of Example 11 using the NegCombo Type 16 panel plate. The direct growth inhibitory effect of rBPI₂₁on these strains was also evaluated in the same assay. Assays wereconducted on clinical isolates of Serratia marcescens (from BaxterMicroscan® library, Sacramento, Calif.).

A summary of the results of the antibiotic screening panels, reported asMICs (μg/ml) of the antibiotic tested, is shown in Table 23 below.Results are reported for each strain tested, but susceptibility data islisted for only those antibiotics for which BPI protein product alteredsusceptibility. The antibiotic susceptibility standards (interpretationof an MIC as resistant, intermediate or susceptible according toMicroscan®'s NCCLS-defived standards) applicable to the organism testedappear in Table 13A. These results show that BPI protein productreversed the resistance of some strains to ceftazidime and cefotaxime,and increased the susceptibility of other strains to piperacillin,cefoxitin, ceftazidime, ceftfiaxone, cefotaxime, tobramycin,ampicillin/sulbactam, and ampicillin.

                  TABLE 23                                                        ______________________________________                                        EFFECTS OF rBPI.sub.21 ± ANTIBIOTICS ON Serratia                           marcescens                                                                                   Minimum                                                                       Inhibitory Concentration                                                      of Antibiotic (μg/mL)                                       Microscan            With     With   With                                     Library Antibiotic   0 μg/mL                                                                             8 μg/mL                                                                           32 μg/mL                              ID No.  Tested       rBPI.sup.21                                                                            rBPI.sub.21                                                                          rBPI.sub.21                              ______________________________________                                        19646   Piperacillin >64      >64      32                                             Cefoxitin      16     >16       8                                             Ceftazidime**                                                                              >16      >16       8                                             Ceftriaxone*   32       16      8                                             Cefotaxime** >32        32    <4                                              Tobramycin*     6        6      4                                     19647   Piperacillin.sup.a                                                                         >64        64     16                                             Cefoxitin       8        8      4                                             Ceftazidime*   16       16      4                                             Ceftriaxone     8      <4     <4                                              Ampicillin/  >16      >16      16                                             Sulbactam                                                                     Cefotaxime      8      <4     < 4                                             Tobramycin      2        2    <1                                      18443   Ampicillin.sup.a                                                                             16       16      8                                             Ampicillin/  >16      >16      16                                             Sulbactam                                                             ______________________________________                                         .sup.a The Microscan ® worksheet did not supply antibiotic                susceptibility ranges for this organism, but there was reversal of            antibiotic indifference according to NCCLS standards, Publication M7A3,       Table 2 (1993).                                                          

EXAMPLE 17 EFFECTS OF BPI PROTEIN PRODUCT AND ANTIBIOTICS IN VITRO ONPROTEUS MIRABILlS

The effect of a BPI protein product, rBPI₂₁, on the antibioticsusceptibility of Proteus mirabilis was evaluated in the Microscan®antibiotic susceptibility screening assay of Example 11 using the NegCombo Type 16 panel plate. The direct growth inhibitory effect of rBPI₂₁on these strains was also evaluated in the same assay. Assays wereconducted on clinical isolates of Proteus mirabilis (from BaxterMicroscan® library, Sacramento, Calif.).

A summary of the results of the antibiotic screening panels, reported asMICs (μg/ml) of the antibiotic tested, is shown in Table 24 below.Results are reported for each strain tested, but susceptibility data islisted for only those antibiotics for which BPI protein product alteredsusceptibility. The antibiotic susceptibility standards (interpretationof an MIC as resistant, intermediate or susceptible according toMicroscan®'s NCCLS-derived standards) applicable to the organism testedappear in Table 13A. These results show that BPI protein productincreased the susceptibility of some strains totrimethoprim/sulfamethoxazole, cefazolin, cefoxitin, imipenem,tobramycin, and amikacin.

                  TABLE 24                                                        ______________________________________                                        EFFECTS OF rBPI.sub.21 ± ANTIBIOTICS ON Proteus                            mirabilis                                                                                    Minimum                                                                       Inhibitory Concentration                                                      of Antibiotic (μg/mL)                                       Microscan            With     With   With                                     Library Antibiotic   0 μg/mL                                                                             8 μg/mL                                                                           32 μg/mL                              ID No.  Tested       rBPI.sup.21                                                                            rBPI.sub.21                                                                          rBPI.sub.21                              ______________________________________                                        19593   Trimethoprim/                                                                              2          <0.5   <0.5                                           Cefazolin    4        <2       4                                              Cefoxitin    8        <2     <2                                               Imipenem*    8        <4     <4                                               Tobramycin   2          2    <1                                               Amikacin     8          4      4                                      F231-129                                                                              Cefoxitin    4        <2       4                                              Imipenem*    8        <4     <4                                               Amikacin     4        <2     <2                                       ______________________________________                                    

EXAMPLE 18 EFFECTS OF BPI PROTEIN PRODUCT AND ANTIBIOTICS IN VITRO ONPROVIDENCIA SPECIES

The effect of a BPI protein product, rBPI₂₁, on the antibioticsusceptibility of various Providencia species was evaluated in theMicroscan® antibiotic susceptibility screening assay of Example 11 usingthe Neg Combo Type 16 panel plate. The direct growth inhibitory effectof rBPI₂₁ on these strains was also evaluated in the same assay. Assayswere conducted on clinical isolates of Providencia species (from BaxterMicroscan® library, Sacramento, Calif.).

A summary of the results of the antibiotic screening panels, reported asMICs (μg/ml) of the antibiotic tested, is shown in Table 25 below.Results are reported for each strain tested, but susceptibility data islisted for only those antibiotics for which BPI protein product alteredsusceptibility. The antibiotic susceptibility standards (interpretationof an MIC as resistant, intermediate or susceptible according toMicroscan®'s NCCLS-defived standards) applicable to the organism testedappear in Table 13A. These results show that BPI protein productreversed the resistance of P. stuartii to cefazolin and cefuroxime, andincreased its susceptibility to piperacillin, ceftazidime,ampicillin/sulbactam, imipenem, and amikacin. BPI protein product alsoincreased susceptibility of P. rettgeri to cefoxitin and cefuroxime.

                  TABLE 25                                                        ______________________________________                                        EFFECTS OF rBPI.sub.21 ± ANTIBIOTICS ON Providencia                        SPECIES                                                                                      Minimum                                                                       Inhibitory Concentration                                                      of Antibiotic (μg/mL)                                       Microscan            With     With   With                                     Library Antibiotic   0 μg/mL                                                                             8 μg/mL                                                                           32 μg/mL                              ID No.  Tested       rBPI.sup.21                                                                            rBPI.sub.21                                                                          rBPI.sub.21                              ______________________________________                                        19614   Cefoxitin    >16         8   >16                                      ( P. rettgeri)                                                                        Cefuroxime*    16        8    <2                                              Amikacin       16       16     16                                     18435   Piperacillin.sup.a                                                                         >64        32     16                                     ( P. stuartii)                                                                        Cefazolin**  >16      >16       8                                             Cefuroxime** >16      >16       8                                             Ceftazidime     4      <2     <2                                              Ampicillin/  >16        16     16                                             Sulbactam                                                                     Imipenem*       8      <4     <4                                              Amikacin       16       16      8                                     ______________________________________                                         .sup.a The Microscan ® worksheet did not supply antibiotic                susceptibility ranges for this organism, but there was reversal of            antibiotic indifference according to NCCLS standards, Publication M7A3,       Table 2 (1993).                                                          

EXAMPLE 19 EFFECTS OF BPI PROTEIN PRODUCT AND ANTIBIOTICS IN VITRO ONMORGANELlA MORGANII

The effect of a BPI protein product, rBPI₂₁, on the antibioticsusceptibility of Morganella morganii was evaluated in the Microscan®antibiotic susceptibility screening assay of Example 11 using the NegCombo Type 16 panel plate. The direct growth inhibitory effect of rBPI₂₁on these strains was also evaluated in the same assay. Assays wereconducted on clinical isolates of Morganella morganii (from BaxterMicroscan® library, Sacramento, Calif.).

A summary of the results of the antibiotic screening panels, reported asMICs (μg/ml) of the antibiotic tested, is shown in Table 26 below.Results are reported for each strain tested, but susceptibility data islisted for only those antibiotics for which BPI protein product alteredsusceptibility. The antibiotic susceptibility standards (interpretationof an MIC as resistant, intermediate or susceptible according toMicroscan®'s NCCLS-derived standards) applicable to the organism testedappear in Table 13A. These results show that BPI protein productincreased the susceptibility of the tested strains toampicillin/sulbactam, amikacin and piperacillin.

                  TABLE 26                                                        ______________________________________                                        EFFECTS OF rBPI.sub.21 ± ANTIBIOTICS ON Morganella                         morganii                                                                                     Minimum                                                                       Inhibitory Concentration                                                      of Antibiotic (μg/mL)                                       Microscan            With     With   With                                     Library Antibiotic   0 μg/mL                                                                             8 μg/mL                                                                           32 μg/mL                              ID No.  Tested       rBPI.sup.21                                                                            rBPI.sub.21                                                                          rBPI.sub.21                              ______________________________________                                        F19-004 Ampicillin/  >16       16     16                                              Sulbactam                                                                     Amikacin        4     <2       4                                      F19-005 Ampicillin/  >16      <8     <8                                               Sulbactam.sup.a                                                               Amikacin        4     <2     <2                                       F19-006 Piperacillin >64       64     64                                              Amikacin      <2      <2       4                                      ______________________________________                                         .sup.a The Microscan ® worksheet did not supply antibiotic                susceptiblity ranges for this organism, but there was reversal of             antibiotic indifference according to NCCLS standards, Publication M7A3,       Table 2 (1993).                                                          

EXAMPLE 20 EFFECTS OF BPI PROTEIN PRODUCT AND ANTIBIOTICS IN VITRO ONACINETOBACTER SPECIES

The effect of a BPI protein product, rBPI₂₁, on the antibioticsusceptibility of various Acinetobacter species was evaluated in theMicroscan® antibiotic susceptibility screening assay of Example 11 usingthe Neg Combo Type 16 and MIC Plus Type 2 panel plate. The direct growthinhibitory effect of rBPI₂₁ on these strains was also evaluated in thesame assay. Assays were conducted on clinical isolates of Acinetobacterspecies (from Baxter Microscan® library, Sacramento, Calif.). Differentproduction lots of rBPI₂₁ that had been formulated with surfactant orunformulated (without surfactant) were tested, but no difference wasseen in results for formulated or unformulated rBPI₂₂.

A summary of the results of the antibiotic screening panels, reported asMICs (μg/ml) of the antibiotic tested, is shown in Tables 27 and 28below. Results are reported for each strain tested, but susceptibilitydata is listed for only those antibiotics for which BPI protein productaltered susceptibility. The antibiotic susceptibility standards(interpretation of an MIC as resistant, intermediate or susceptibleaccording to Microscan®'s NCCLS-derived standards) applicable to theorganism tested appear in Tables 13A and 14A. For interpretationpurposes, when antibiotic susceptibility standards were given only forEnterobacter or Pseudomonas, the standards for Acinetobacter wereconsidered to be the same as for Enterobacter.

These results show that BPI protein product reversed resistance of A.anitratus strains to amoxicillin/K clavulanate, ampicillin/sulbactam,aztreonam, carbenlcillin, cefamandole, cefazolin, cefonicid,cefoperazone, cefotaxime, cefotetan, cefoxitin, ceftazidime,ceftizoxime, ceftriaxone, chloramphenicol, ciprofloxacin, gentamicin,mezlocillin, netilmicin, ticarcillin, ticarcillin/K clavulanate, andtfimethopfim/sulfamethoxazole, and increased susceptibility of some A.anitratus strains to amikacin, amoxicillin/K clavulanate, ampicillin.ampicillin/sulbactam, azlocillin, aztreonam, carbenicillin, cefamandole,cefazolin, cefonicid, cefoperazone, cefotaxime, cefotetan, cefoxitin,ceftazidime, cefiizoxime, ceftriaxone, cefuroxime, chloramphenicol,ciprofloxacin, gentamicin, imipenem, mezlocillin, netfirnicin,ofloxacin, piperacillin, ticarcfilin, ticarcillin/K clavulanate,tobramycin and trimethoprim/suffamethoxazole.

BPI protein product reversed resistance of A. lwoffii strains toaztreonam, cefazolin, cefuroxime, ceftazidime, cefoxitin,trimethoprim/suffamethoxazole and piperacillin, and increasedsusceptibility of A. lwoffii strains to ampicillin,ampicillin/sulbactam, aztreonam, cefazolin, cefotaxime, cefoxitin,ceftazidime, cefiriaxone, cefuroxime, pipemcillin, ticarcillin andtrimethoprim/suffamethoxazole.

These results also show that rBPI₂₁ at a concentration of 16 μg/ml hasdirect bactericidal/growth inhibitory effects on some of the testedAcinetobacter isolates.

                  TABLE 27                                                        ______________________________________                                        EFFECTS OF rBPI.sub.21 ± ANTIBIOTICS ON Acinetobacter                      SPECIES                                                                                      Minimum                                                                       Inhibitory Concentration                                                      of Antibiotic (μg/mL)                                       Microscan            With     With   With                                     Library  Antibiotic  0 μg/mL                                                                             4 μg/mL                                                                           16 μg/mL                              ID No.   Tested      rBPI.sup.21                                                                            rBPI.sub.21                                                                          rBPI.sub.21                              ______________________________________                                        N011-002 BPI         G        G      G                                        ( A. anitratus)                                                                        Ampicillin  >16      16     16                                                Amikacin    4        <2     <2                                       N011-003 BPI         G        G      G                                        (A. anitratus)                                                                         Ampicillin  4        <2     4                                                 Ticarcillin 16       <8     <8                                                Cefazolin** >16      >16    8                                                 Cefoxitin** >16      8      8                                                 Cefuroxime  8        4      8                                        N011-070 BPI         G        Reduced                                                                              NG                                       (A. anitratus)                                                                         Ampicillin  8        8      <2                                                Trimeth/    >2       2      <0.5                                              Sulfa**                                                                       Cefazolin** >16      >16    <2                                                Cefoxitin*  16       16     <2                                                Cefuroxime* 16       8      <2                                                Ceftazidime 4        <2     <2                                       N011-071 BPI         G        G      Very                                     (A. anitratus)                       reduced                                           Ticarcillin*                                                                              32       <8     <8                                                Aztreonam   > 16     16     16                                                Piperacillin*                                                                             32       16     <8                                                Ciprofloxacin**                                                                           >2       2      <1                                                Ofloxacin*  4        <2     <2                                                Ceftazidime 8        8      4                                                 Ceftriazone 32       16     16                                                Cefotaxime  32       16     16                                                Gentamicin**                                                                              >6       >6     2                                                 Tobramycin* 6        4      4                                                 Amikacin**  >16      16     8                                        N011-072 BPI         G        Reduced                                                                              NG                                       (A. anitratus)                                                                         Ampicillin* 16       16     <2                                                Trimeth/    >2       >2     <0.5                                              Sulfa**                                                                       Cefazolin** >16      >16    <2                                                Cefoxitin*  16       16     <2                                                Cefuroxime  8        8      <2                                                Gentamicin* 6        4      <1                                                Tobramycin  2        <2     <2                                                Amikacin    8        4      <2                                       N012-001 BPI         G        G      G                                        (A. lwoffii)                                                                           Aztreonam** >16      >16    <8                                                Cefazolin** >16      8      <2                                                Cefuroxime**                                                                              >16      4      <2                                                Ceftazidime**                                                                             >16      4      <2                                                Ampicill/   >16      >16    16                                                Sulbact                                                                       Cefotaxime  8        <4     <4                                       N012-002 BPI         G        NG     NG                                       (A. lowffii)                                                                           Ampicillin  4        <2     <2                                                Trimeth/    >2       2      <0.5                                              Sulfa**                                                                       Aztreonam** >16      <8     <8                                                Cefazolin** >16      <2     <2                                                Cefoxitin** >16      <2     <2                                                Cefuroxime  8        <2     <2                                                Ceftazidime 4        <2     <2                                       N012-003 BPI         G        G      NG                                       (A. lwoffii)                                                                           Ampicillin* >16      4      <2                                                Trimeth/    2        <0.5   <0.5                                              Sulfa*                                                                        Ticarcillin*                                                                              64       <8     <8                                                Aztreonam** >16      <8     <8                                                Piperacillin**                                                                            >64      <8     <8                                                Cefazolin** >16      >16    <2                                                Cefoxitin** >16      8      <2                                                Cefuroxime**                                                                              >16      <2     <2                                                Ceftazidime*                                                                              16       <2     <2                                                Ceftriazone*                                                                              16       <4     <4                                                Cefotaxime  8        <4     <4                                       N012-004 BPI         G        G      G                                        (A. lwoffii)                                                                           Ampicillin  4        <2     4                                                 Trimeth/    2        2      <0.5                                              Sulfa*                                                                        Cefazolin   >16      16     16                                                Cefoxitin*  16       <2     4                                                 Cefuroxime  4        <2     <2                                       N012-005 BPI         G        G      NG                                       (A. lwoffii)                                                                           Ampicillin  4        <2     <2                                                Trimeth/    2        <0.5   <0.5                                              Sulfa*                                                                        Cefazolin** >16      >16    4                                                 Cefoxitin*  16       8      4                                                 Cefuroxime  4        4      <2                                       ______________________________________                                    

                  TABLE 28                                                        ______________________________________                                        EFFECTS OF rBPI.sub.21 ± ANTIBIOTICS ON Acinetobacter                      SPECIES                                                                                      Minimum                                                                       Inhibitory Concentration                                                      of Antibiotic (μg/mL)                                       Microscan            With     With   With                                     Library  Antibiotic  0 μg/mL                                                                             4 μg/mL                                                                           16 μg/mL                              ID No.   Tested      rBPI.sup.21                                                                            rBPI.sub.21                                                                          rBPI.sub.21                              ______________________________________                                        12292    Ceftizoxime**                                                                             >32      <2     <2                                       ( A. anitratus)                                                                        Ceftazidime**                                                                             >32      32     <1                                                Cefotaxime**                                                                              >64      8      <2                                                Ceftriaxone**                                                                             >64      <2     <2                                                Cefoperazone**                                                                            >32      8      <4                                                Cefonicid** >16      16     <2                                                Cefotetan** >32      32     <4                                                Netilmicin**                                                                              >16      <2     <2                                                Cefamandole**                                                                             >32      <4     <4                                                Chloram-    >16      <2     <2                                                phenicol**                                                                    Ticarcillin*                                                                              64       32     <16                                               Azlocillin  >64      <64    <64                                               Imipenem    4        <0.5   <0.5                                              Amp/Sulbact**                                                                             32       4      <1                                                Aztreonam** 32       4      <1                                                Amox/K      16       <1     <1                                                Clavulanate*                                                                  Ciprofloxacin**                                                                           >4       1      <25                                               Ticar/K     64       <16    <16                                               Clavulanate**                                                                 Mezlocillin**                                                                             >128     <16    <16                                               Carbenicillin**                                                                           >128     <16    <16                                      12300    Ceftizoxime**                                                                             >32      >32    <8                                       (A. anitratus)                                                                         Ceftazidime 8        8      2                                                 Cefotaxime**                                                                              64       64     <2                                                Ceftriaxone*                                                                              32       32     <2                                                Cefoperazone                                                                              >32      >32    32                                                Cefonicid   >16      >16    >16                                               Cefotetan   >32      >32    >32                                               Netilmicin  >16      16     16                                                Cefamandole**                                                                             >32      >32    <4                                                Chlor-      >16      >16    8                                                 amphenicol**                                                                  Ticarcillin <16      <16    <16                                               Azlocillin  >64      <64    <64                                               Imipenem    <0.5     <0.5   <0.5                                              Amp/Sulbact 2        2      <1                                                Aztreonam   8        8      4                                                 Amox/K      16       16     <1                                                Clavulanate*                                                                  Aiprofloxacin**                                                                           >4       >4     1                                                 Ticar/K     <16      <16    <16                                               Clavulante                                                                    Mezlocillin**                                                                             128      128    <16                                               Carbenicillin                                                                             <16      <16    <16                                      12487    Ceftizoxime**                                                                             >32      >32    <2                                       (A. anitratus)                                                                         Ceftazidime**                                                                             >32      2      8                                                 Cefotaxime**                                                                              >64      64     4                                                 Ceftriaxone**                                                                             >64      >64    <2                                                Cefoperazone**                                                                            >32      >32    <4                                                Cefonicid   >16      >16    >16                                               Cefotetan   >32      >32    32                                                Netilmicin**                                                                              >16      <2     <2                                                Cefamandole**                                                                             <32      <4     <4                                                Chlor-      >16      8      <2                                                amphenicol**                                                                  Ticarcillin**                                                                             128      32     <16                                               Azlocillin  >64      <64    <64                                               Imipenem    2        <0.5   <0.5                                              Amp/Sulbact*                                                                              16       2      <1                                                Aztreonam** 32       16     <1                                                Amox/K      8        <1     2                                                 Clavulanate                                                                   Ciprofloxacin*                                                                            2        1      <0.25                                             Ticar/K     32       <16    <16                                               Clavulanate                                                                   Mezlocillin**                                                                             >128     32     <16                                               Carbenicillin**                                                                           128      <16    <16                                      19687    Ceftizoxime >32      >32    >32                                      (A. anitratus)                                                                         Ceftazidime >32      >32    >32                                               Cefotaxime  >64      >64    >64                                               Ceftriaxone >64      >64    >64                                               Cefoperazone                                                                              >32      >32    >32                                               Cefonicid   >16      >16    >16                                               Cefotetan   >32      >32    >32                                               Netilmicin* 16       8      <2                                                Cefamandole >32      >32    >32                                               Chlor-      >16      6      8                                                 amphenicol**                                                                  Ticarcillin >128     <16    128                                               Azlocillin  >64      >64    >64                                               Imipenem    4        2      <0.5                                              Amp/Sulbact**                                                                 Aztreonam   >32      >32    >32                                               Amox/K      32       16     8                                                 Clavulanate**                                                                 Ciprofloxacin**                                                                           >4       >4     0.5                                               Ticar/K     >128     128    <16                                               Clavulanate                                                                   Mezlocillin >128     64     32                                                Carbenicillin**                                                                           >128     64     <16                                      19693    Ceftizoxime**                                                                             >32      >32    4                                        (A. anitratus)                                                                         Ceftazidime >32      >32    >32                                               Cefotaxime  >64      64     32                                                Ceftriaxone >64      64     16                                                Cefoperazone**                                                                            >32      >32    8                                                 Cefonicid** >16      >16    <2                                                Cefotetan** >32      >32    <4                                                Netilmicin  >16      >16    >16                                               Cefamandole >32      >32    16                                                Chlo-       >16      >16    <2                                                amphenicol**                                                                  Ticarcillin**                                                                             >128     >128   <16                                               Azlocillin  >64      >64    <64                                               Imipenem    2        2      <0.5                                              Amp/Sulbact**                                                                             32       16     <1                                                Amox/K      16       8      4                                                 Clavulanate*                                                                  Ciprofloxacin                                                                             >4       >4     >4                                                Ticar/K     >128     32     <16                                               Clavulanate**                                                                 Mezlocillin**                                                                             >128     128    <16                                               Carbenicillin                                                                             > 128    >128   <16                                      19694    Ceftizoxime >32      >32    32                                       (A. anitratus)                                                                         Ceftazidime*                                                                              16       16     8                                                 Cefotaxime  64       64     64                                                Ceftriaxone 64       64     32                                                Cefoperazone                                                                              >32      >32    >32                                               Cefonicid** >16      >16    8                                                 Cefotetan** >32      >32    8                                                 Netilmicin**                                                                              >16      >16    4                                                 Cefamandole >32      >32    >32                                               Chlor-      >16      >16    16                                                amphenicol                                                                    Ticarcillin >128     >128   32                                                Azlocillin  >64      >64    >64                                               Imipenem    1        1      <0.5                                              Amp/Sulbact 32       32     16                                                Aztreonam   8        8      8                                                 Amox/K      32       8      4                                                 Clavulanate**                                                                 Ciprofloxacin                                                                             >4       >4     >4                                                Ticar/K     >128     <16    <16                                               Clavulanate**                                                                 Mezlocillin >128     >128   64                                                Carbenicillin**                                                                           >128     >128   <16                                      ______________________________________                                    

EXAMPLE 21 EFFECTS OF BPI PROTEIN PRODUCT AND ANTIBIOTICS IN VITRO ONSALMONELLA AND SHIGELLA SPECIES

Ten clinical isolates of Salmonella (F270-001 through -010) and 10clinical isolates of Shigella (F321-010 and F325-002 through -010) (allisolates from Baxter Microscan® library, Sacramento, Calif.), wereevaluated in the Microscan® antibiotic susceptibility screening assay ofExample 11 using the Neg Breakpoint Combo Type 9 panel plate.Essentially no effect was seen at rBPI₂₁ concentrations of 0, 4 and 16μg/mL.

EXAMPLE 22 EFFECTS OF BPI PROTEIN PRODUCT ON ANTIBIOTIC KILLING CURVESFOR E. COLI J5, E. COLI O7:K1, ENTEROBACTER CLOACAE, AND KLEBSIELLAPNEUMONIAE

The effect of a BPI protein product, rBPI₂₁, on the killing curves ofselected antibiotics was determined for selected organisms. Microscan®panel plates were prepared for E. coli J5, E. coli O7:K1, Enterobactercloacae (Microscan library ID no. 19680) and Klebsiella pneumoniae(Microscan library ID no. 16135), according to Example 11. Cellsuspensions were added to 25 ml Pluronic Inoculum Water containing 0 or16 μg/ml rBPI₂₁. After inoculation, the panel plates were incubated at35° C. for 24 hours. At 0, 4, 7 and 24 hours after inoculation, 5 μlsamples were removed from each growth control well (containing culturemedia without antibiotic) and from each well containing: 2/38 μg/mltrimethoprim/sulfamethoxazole, 2 μg/ml ciprofloxacin, 64 μg/mlpiperacillin, 32 μg/ml cefotaxime, 6 μg/ml cefuroxime, and 16 μg/mlamikacin. These 5 μl samples were diluted in sterile water andinoculated onto Trypticase Soy agar plates (Remel, Lenexa, Kansas).After 48 hours of incubation at 35° C., the plates were counted and thenumber of colony forming units of bacteria in the well was calculated.

The results are shown below in FIGS. 19-25. In all of the figures thegrowth, in the presence of antibiotic but without rBPI₂₁, is indicatedfor: E. coli J5 (a filled square): E. coli O7:K1 (a filled diamond); E.cloacae (a filled triangle); and K. pneumoniae (an "X"). Also, in allfigures, the growth in the presence of antibiotic with rBPI²¹ isindicated for E. coli J5 (an open square); E. coli O7:K1 (an opendiamond); E. cloacae (an open triangle); and K. pneumoniae (a star).

FIG. 19 shows the kinetic growth curve of organisms with rBPI₂₁ (andwithout antibiotic) and without rBPI₂₁ (and without antibiotic). In FIG.19, the growth curves for E. coli J5 without rBPI₂₁ (filled squares), E.coli O7:K1 with rBPI₂₁ (open diamonds), E. coli O7:K1 without rBPI₂₁(filled diamonds), and K. pneumoraae without rBPI₂₁ ("X"s) overlapsubstantially, while the growth curves for E. coli J5 with rBPI₂₁ (opensquares) and E. cloacae with rBPI₂₁ (open triangles) overlap at 0-7hours but diverge by 24 hours. FIG. 19 demonstrates that BPI proteinproduct alone has a bactericidal effect at 0-7 hours on E. coli J5 andK. pneumoniae, and a bactericidal effect on E. cloacae throughout the 24hour period studied.

In FIG. 20, the growth curves for E. coli J5 with rBPI₂₁ (open squares),E. cloacae with rBPI₂₁ (open triangles) and K. pneumoniae with rBPI₂₁(stars) overlap. FIG. 20 shows that rBPI₂₁ enhanced the bactericidaleffect of trimethoprim/sulfamethoxazole on E. cloacae and K. pneumoniaeat 0-24 hours, and slightly enhanced the antibiotics' effect on E. coliJ5 and E. coli O7:K1.

In FIG. 21, the growth curves for E. coli J5 with rBPI₂₁ (open squares),E. coli J5 without rBPI₂₁ (filled squares), E. coli O7:K1 with rBPI₂₁(open diamonds), E. coil O7:K1 without rBPI₂₁ (filled diamonds), E.cloacae with rBPI₂₁ (open triangles), E. cloacae without rBH₂₁ (filledtriangles), and K. pneumoniae with rBPI₂₁ (stars) overlap. FIG. 21 showsthat rBPI₂₁ reversed resistance of K. pneumoniae to ciprofioxacin at0-24 hours; the other organisms were already very susceptible tociprofloxacin.

In FIG. 22, the growth curves for E. coli O7:K1 without rBPI₂₁ (filleddiamonds) and E. cloacae without rBPI₂₁ (filled triangles) overlap,while the growth curves for E. coli J5 with rBPI₂₁ (open squares), E.coli J5 without rBPI₂₁ (filled squares), E. coli O7:K1 with rBPI₂₁ (opendiamonds), E. cloacae with rBPI₂₁ (open triangles), K. pneumoniaewithout rBPI₂₁ ("X"s) and K. pneumoniae with rBPI₂₁ (stars) overlap.FIG. 22 shows that rBPI₂₁ enhanced the bactericidal effect ofpiperacillin on E. coli O7:K1 and E. cloacae; the other organisms werealready susceptible to the drug.

In FIG. 23, the growth curves for E. coli J5 with rBPI₂₁ (open squares),E. coli O7:K1 with rBPI₂₁ (open diamonds), E. coli O7:K1 without rBPI₂₁(filled diamonds), K. pneumoniae without rBPI₂₁ ("X"s) and K. pneumoniaewith rBPI₂₁ (stars) overlap. FIG. 23 shows that rBPI₂₁ enhanced thebactericidal effect of cefotaxime on J5 and E. cloacae; the otherorganisms were susceptible to the drug.

In FIG. 24, all of the curves overlap. FIG. 24 shows the effect of rBPI₂and cefuroxime; addition of rBPI₂₁ had no effect on the killing curvesbecause all of the tested species were very susceptible to theantibiotic.

In FIG. 25, all of the curves overlap. FIG. 25 shows the effect ofrBPI₂₁ and amikacin; again, all tested species were very susceptible tothe antibiotic.

EXAMPLE 23 EFFECTS OF A VARIETY OF BPI PROTEIN PRODUCTS AND ANTIBIOTICSIN VITRO ON REPRESENTATIVE GRAM-NEGATIVE ORGANISMS

The effects of a variety of BPI protein products, rBPI₂₁, rBPI₂₃, rBPI₅₀and rBPI₄₂ dimer on the antibiotic susceptibility of variousrepresentative gram-negative organisms was evaluated in the Microscan®antibiotic susceptibility screening assay of Example 11 using the MICPlus Type 2 panel plate. Assays were conducted on clinical isolates ofAcinetobacter anitratus and Enterobacter cloacae (from Baxter Microscan®library, Sacramento, Calif.), and on E. coli J5-L and O7:K1.

The results, reported as MICs (μg/ml) of the antibiotic tested at thevarious concentrations of BPI protein product indicated, are shown inTables 29, 30, 31 and 32 below.

                                      TABLE 29                                    __________________________________________________________________________    EFFECTS OF BPI PROTEIN PRODUCTS ± ANTIBIOTICS ON A. anitratus              (Microscan ID No. 12292)                                                               Minimum Inhibitory Concentration of Antibiotic (μg/ml) With:               0   4   4   4   4 μg/mL                                                                         16  16  16  16 μg/mL                         ANTIBIOTIC                                                                             μg/mL                                                                          μg/mL                                                                          μg/mL                                                                          μg/mL                                                                          BPI.sub.42                                                                         μg/mL                                                                          μg/mL                                                                          μg/mL                                                                          BPI.sub.42μg/mL                  TESTED   BPI BPI.sub.21                                                                        BPI.sub.23                                                                        BPI.sub.50                                                                        dimer                                                                              BPI.sub.21                                                                        BPI.sub.23                                                                        BPI.sub.50                                                                        dimer                               __________________________________________________________________________    Ceftizoxime                                                                            >32 >32 >32 >32 >32  >32 <32 <32 >32                                 Ceftazidime                                                                            >32 16  >32 >32 >32  32  >32 >32 32                                  Cefotaxime                                                                             >64 >64 >64 >64 >64  16  >64 >64 >64                                 Ceftriaxone                                                                            >64 8   >64 >64 >64  4   >64 >64 >64                                 Cefoperazone                                                                           >32 >32 >32 >32 >32  32  >32 >32 >32                                 Cefonicid                                                                              >16 >16 >16 >16 > 16 8   >16 >16 >16                                 Cefotetan                                                                              >32 32  >32 >32 >32  <4  >32 >32 >32                                 Netilmicin                                                                             >16 <2  >16 >16 >16  >16 >16 >16 >16                                 Cefamandole                                                                            >32 8   >32 >32 >32  <4  >32 >32 >32                                 Chloramphenicol                                                                        >16 <2  >16 16  >16  <2  16  16  16                                  Ticarcillin                                                                            128 <16 128 64  64   <16 64  32  64                                  Azlocillin                                                                             >64 >64 >64 >64 >64  <64 >64 >64 >64                                 Imipenem 4   <0.5                                                                              2   2   2    <0.5                                                                              2   2   2                                   Ampicillin/                                                                            32  4   16  32  16   <1  8   16  8                                   Sulbactam                                                                     Aztreonam                                                                              32  16  32  32  32   4   32  32  32                                  Amoxicillin/K                                                                          16  2   16  16  8    4   8   8   4                                   Clavulanate                                                                   Ciprofloxacin                                                                          4   2   4   4   4    2   4   4   2                                   Ticarcillin/K                                                                          64  <16 64  64  32   32  32  32  32                                  Clavulanate                                                                   Mezlocillin                                                                            >128                                                                              128 >128                                                                              >128                                                                              >128 <16 >128                                                                              >128                                                                              >128                                Carbenicillin                                                                          128 <16 128 128 64   <16 64  64  64                                  __________________________________________________________________________

                                      TABLE 30                                    __________________________________________________________________________    EFFECTS OF BPI PROTEIN PRODUCTS ± ANTIBIOTICS ON E. cloacae (Microscan     ID No. 19680)                                                                          Minimum Inhibitory Concentration of Antibiotic (μg/ml) With:               0    4    4    4    4 μg/mL                                                                         16   16   16   16 μg/mL                  ANTIBIOTIC                                                                             μg/mL                                                                           μg/mL                                                                           μg/mL                                                                           μg/mL                                                                           BPI.sub.42                                                                         μg/mL                                                                           μg/mL                                                                           μg/mL                                                                           BPI.sub.42μg/mL           TESTED   BPI  BPI.sub.21                                                                         BPI.sub.23                                                                         BPI.sub.50                                                                         dimer                                                                              BPI.sub.21                                                                         BPI.sub.23                                                                         BPI.sub.50                                                                         dimer                        __________________________________________________________________________    Ceftizoxime                                                                            32   32   32   16   32   <2   <2   <2   8                            Ceftazidime                                                                            32   16   16   32   16   <1   <1   <1   4                            Cefotaxime                                                                             64   32   32   32   32   <2   <2   <2   16                           Ceftriaxone                                                                            32   4    32   32   32   <2   <2   <2   16                           Cefoperazone                                                                           32   16   16   16   32   <4   <4   <4   <4                           Cefonicid                                                                              >16  >16  >16  >16  >16  <2   <2   8    >16                          Cefotetan                                                                              32   >32  >32  >32  >32  <4   < 4  <4   >32                          Netilmicin                                                                             <2   <2   <2   <2   <2   <2   <2   <2   <2                           Cefamandole                                                                            >32  >32  32   >32  >32  <4   <4   <4   16                           Chloramphenicol                                                                        8    4    4    4    4    <2   <2   <2   <2                           Ticarcillin                                                                            >128 64   64   128  128  <16  <16  <16  64                           Azlocillin                                                                             >64  >64  <64  >64  >64  <64  <64  <64  <64                          Imipenem 1    <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0,5                         Ampicillin/                                                                            >32  >32  >32  32   >32  2    2    4    32                           Sulbactam                                                                     Aztreonam                                                                              32   8    4    32   16   <1   <1   <1   16                           Amoxicillin/K                                                                          32   32   32   32   32   8    8    16   >32                          Clavulanate                                                                   Ciprofloxacin                                                                          <.25 <.25 <.25 <.25 <.25 <.25 <.25 <.25 <.25                         Ticarcillin/K                                                                          >128 64   128  128  128  <16  <16  <16  32                           Clavulanate                                                                   Mezlocillin                                                                            <16  <16  <16  <16  <16  <16  <16  <16  <16                          Carbenicillin                                                                          >128 128  64   128  128  <16  <16  <16  128                          __________________________________________________________________________

                                      TABLE 31                                    __________________________________________________________________________    EFFECTS OF BPI PROTEIN PRODUCTS ± ANTIBIOTICS ON E. coli J5-L                       Minimum Inhibitory Concentration of Antibiotic (μg/ml) With:               0   4   4   4   4 μg/mL                                                                         16  16  16  16 μg/mL                         ANTIBIOTIC                                                                             μg/mL                                                                          μg/mL                                                                          μg/mL                                                                          μg/mL                                                                          BPI.sub.42                                                                         μg/mL                                                                          μg/mL                                                                          μg/mL                                                                          BPI.sub.42μg/mL                  TESTED   BPI BPI.sub.21                                                                        BPI.sub.23                                                                        BPI.sub.50                                                                        dimer                                                                              BPI.sub.21                                                                        BPI.sub.23                                                                        BPI.sub.50                                                                        dimer                               __________________________________________________________________________    Ceftizoxime                                                                            <2  <2  <2  <2  <2   <2  <2  <2  <2                                  Ceftazidime                                                                            <1  <1  <1  <1  <1   <1  <1  <1  <1                                  Cefotaxime                                                                             <2  <2  <2  <2  <2   <2  <2  <2  <2                                  Ceftriaxone                                                                            <2  <2  <2  <2  <2   <2  <2  <2  <2                                  Cefoperazone                                                                           <4  <4  <4  <4  <4   <4  <4  <4  <4                                  Cefonicid                                                                              <2  <2  <2  <2  <2   <2  <2  <2  <2                                  Cefotetan                                                                              <4  <4  <4  <4  <4   <4  <4  <4  <4                                  Netilmicin                                                                             <2  <2  <2  <2  <2   <2  <2  <2  <2                                  Cefamandole                                                                            <4  <4  <4  <4  <4   <4  <4  <4  <4                                  Chloramphenicol                                                                        <2  <2  <2  <2  <2   <2  <2  <2  <2                                  Ticarcillin                                                                            <16 <16 <16 <16 <16  <16 <16 <16 <16                                 Azlocillin                                                                             <64 <64 <64 <64 <64  <64 <64 <64 <64                                 Imipenem <0.5                                                                              <0.5                                                                              <0.5                                                                              <0.5                                                                              <0.5 <0.5                                                                              <0.5                                                                              <0.5                                                                              <0.5                                Ampicillin/                                                                            2   2   2   2   2    <1  <1  <1  2                                   Sulbactam                                                                     Aztreonam                                                                              <1  <1  <1  <1  <1   <1  <1  <1  <1                                  Amoxicillin/K                                                                          4   <1  2   4   2    <1  <1  2   2                                   Clavulanate                                                                   Ciprofloxacin                                                                          <.25                                                                              <.25                                                                              < .25                                                                             <.25                                                                              <.25 <.25                                                                              <.25                                                                              <.25                                                                              <.25                                Ticarcillin/K                                                                          <16 <16 <16 <16 <16  <16 <16 <16 <16                                 Calvulanate                                                                   Mezlocillin                                                                            <16 <16 <16 <16 <16  <16 <16 <16 <16                                 Carbenicillin                                                                          <16 <16 <16 <16 <16  <16 <16 <16 <16                                 __________________________________________________________________________

                                      TABLE 32                                    __________________________________________________________________________    EFFECTS OF BPI PROTEIN PRODUCTS ± ANTIBIOTICS ON E. coli O7:K1                      Minimum Inhibitory Concentration of Antibiotic (μg/ml) With:               0   4   4   4   4 μg/mL                                                                         16  16  16  16 μg/mL                         ANTIBIOTIC                                                                             μg/mL                                                                          μg/mL                                                                          μg/mL                                                                          μg/mL                                                                          BPI.sub.42                                                                         μg/mL                                                                          μg/mL                                                                          μg/mL                                                                          BPI.sub.42μg/mL                  TESTED   BPI BPI.sub.21                                                                        BPI.sub.23                                                                        BPI.sub.50                                                                        dimer                                                                              BPI.sub.21                                                                        BPI.sub.23                                                                        BPI.sub.50                                                                        dimer                               __________________________________________________________________________    Ceftizoxime                                                                            <2  <2  <2  <2  <2   <2  <2  <2  <2                                  Ceftazidime                                                                            <1  <1  <1  <1  <1   <1  <1  <1  <1                                  Cefotaxime                                                                             <2  <2  <2  <2  <2   <2  <2  <2  <2                                  Ceftriaxone                                                                            <2  <2  <2  <2  <2   <2  <2  <2  <2                                  Cefoperazone                                                                           <4  <4  <4  <4  <4   <4  <4  <4  <4                                  Cefonicid                                                                              <2  <2  <2  <2  <2   <2  <2  <2  <2                                  Cefotetan                                                                              <4  <4  <4  <4  <4   <4  <4  <4  <4                                  Netilmicin                                                                             <2  <2  <2  <2  <2   <2  <2  <2  <2                                  Cefamandole                                                                            <4  <4  <4  <4  <4   <4  <4  <4  <4                                  Chloramphenicol                                                                        <2  <2  <2  <2  <2   <2  <2  <2  <2                                  Ticarcillin                                                                            <16 <16 <16 <16 <16  <16 <16 <16 <16                                 Azlocillin                                                                             <64 <64 <64 <64 <64  <64 <64 <64 <64                                 Imipenem <0.5                                                                              <0.5                                                                              <0.5                                                                              <0.5                                                                              <0.5 <0.5                                                                              <0.5                                                                              <0.5                                                                              <0.5                                Ampicillin/                                                                            <1  <1  <1  <1  <1   <1  <1  <1  <1                                  Sulbactam                                                                     Aztreonam                                                                              <1  <1  <1  <1  <1   <1  <1  <1  <1                                  Amoxicillin/K                                                                          <1  <1  <1  <1  <1   <1  < 1 <1  <1                                  Clavulanate                                                                   Ciprofloxacin                                                                          <.25                                                                              <.25                                                                              <.25                                                                              <.25                                                                              <.25 <.25                                                                              <.25                                                                              <.25                                                                              <.25                                Ticarcillin/K                                                                          <16 <16 <16 <16 <16  <16 <16 <16 <16                                 Clavulanate                                                                   Mezlocillin                                                                            <16 <16 <16 <16 <16  <16 <16 <16 <16                                 Carbenicillin                                                                          <16 <16 <16 <16 <16  <16 <16 <16 <16                                 __________________________________________________________________________

EXAMPLE 24 GRAM-NEGATIVE BACTERICIDAL ACTIVITY OF BPI PEPTIDES

BPI peptides were produced according to co-owned and copending PCTApplication No. PCT US94/10427 filed Sep. 15, 1994, which corresponds toU.S. patent application Ser. No. 08/306,473 filed Sep. 15, 1994, and PCTApplication No. US94/02465 filed Mar. 11, 1994, which corresponds toU.S. patent application Ser. No. 08/209,762, filed Mar. 11, 1994, whichis a continuation-in-pan of U.S. patent application Ser. No. 08/183,222,filed Jan. 14, 1994, which is a continuation-in-part of U.S. patentapplication Ser. No. 08/093,202 filed Jul. 15, 1993 (for which thecorresponding international application is PCT Application No.US94/02401 filed Mar. 11, 1994), which is a continuation-in-part of U.S.patent application Ser. No. 08/030,644 filed Mar. 12, 1993, thedisclosures of all of which are incorporated herein by reference.

The BPI peptides were screened for bactericidal effects on E. coli J5and E. Coli 0111:B4 bacteria in a radial diffusion assay. Specifically,an overnight culture of the bacteria was diluted 1:50 into fresh trypticsoy broth and incubated for 3 hours at 3° C. to attain log phase growthof the culture. Bacteria were then pelleted at 3,000 rpm for 5 minutesin a Sorvall RT6000B centrifuge (Sorvall Instruments, Newton, TC). 5 mLof 10 mM sodium phosphate buffer (pH 7.4) was added and the preparationwas re-pelleted. The supernatant was decanted and 5 mL of fresh bufferwas added, the bacteria were resuspended and their concentration wasdetermined by measurement of absorbance at 590 nm (an Absorbance valueof 1.00 at this wavelength equals a concentration of about 1.25×10⁹CFU/mL in suspension). The bacteria were diluted to 4×10⁶ CFU/mL in 10mL of molten underlayer agarose (at approximately 45° C.) and invertedrepeatedly to mix in 15 mL polypropylene tubes conventionally used forthis purpose.

The entire contents of such tubes were then poured into a level squarepetri dish and distributed evenly by rocking the dish side-to-side. Theagarose hardened in less than 30 seconds and had a uniform thickness ofabout 1 mm. A series of wells were then punched into the hardenedagarose using a sterile 3 mm punch attached to a vacuum apparatus. Thepunch was sterilized with 100% alcohol and allowed to air dry prior touse to avoid contaminating the bacterial culture.

5 or 10 μL of each of the BPI peptides were carefully pipetted into eachwell. As a negative control, dilution buffer (pH 8.3) was added to aseparate well, and rBPI₂₃ at concentrations of 5 μg/mL and 1 μg/mL werealso added as positive controls. Each plate was incubated at 37° C. for3 hours, and then 10 mL of molten overlayer agarose (at approximately45° C.) was added into the level petri dish, allowed to harden andincubated overnight at 37° C. The next day, a clear zone was seenagainst the lawn of bacteria in those wells having bactericidalactivity. In order to visually enhance this zone, a dilute Coomassiesolution (consisting of 0.002% Coomassie Brilliant Blue, 27% methanol.15% formaldehyde (37% stock solution) and water) was poured over theagar and allowed to stain for 24 hours. The bacterial zones weremeasured with a micrometer. The assay results for exemplary peptides(BPI. 1 through BPI. 169) are summarized in Table 33 for theGram-negative bacteria E. coli J5 (rough) and E. coli O113 (smooth). Thebactericidal activities are expressed as the amount of peptide(pmol/well and μg/well) required to generate a 30 mm² bactericidal zone.Additional exemplary BPI peptides include BPI.221 through BPI.281. BPIpeptides which retain antibacterial activity are expected to improve thetherapeutic effectiveness of antibiotics when concurrently administeredtherewith. The peptides are screened for such activity in an in vivomodel or according to in vitro tests, including models and testsdescribed herein.

                                      TABLE 33                                    __________________________________________________________________________    Bacteridical Activity.sup.a                                                   BPI  Sequence                                                                            E. coli J5  E. coli O111:B4                                        Peptide                                                                            ID No.                                                                             (pmol/well)                                                                          (μg/well)                                                                        (pmol/well)                                                                          (μg/well)                                    __________________________________________________________________________    BPI.1                                                                               4   --.sup.b                                                                             --    --     --                                              BPI.2                                                                               7   >2733.5                                                                              >5    --     --                                              BPI.3                                                                               11  696    2.14  --     --                                              BPI.4                                                                               3   --     --    --     --                                              BPI.5                                                                               67  398    1.05  >1904  >5                                              BPI.7                                                                               54  175    0.46  >1890.6                                                                              >5                                              BPI.8                                                                               8   >3797.1                                                                              >5    --     --                                              BPI.9                                                                               51  479    1.02  >2345.9                                                                              >5                                              BPI.10    102    0.41  697    2.76                                            BPI.11                                                                              13  638    1.06  --     --                                              BPI.12                                                                              14  525    1.78  --     --                                              BPI.13                                                                              15  441    0.75  >2923.9                                                                              >5                                              BPI.14                                                                              2   --     --    --     --                                              BPI.15                                                                              16  >2797.8                                                                              >5    --     --                                              BPI.16                                                                              17  >2821.5                                                                              >5    --     --                                              BPI.17                                                                              18  >2807.2                                                                              >5    --     --                                              BPI.18                                                                              19  >2757.6                                                                              >5    --     --                                              BPI.19                                                                              20  >2712.8                                                                              >5    --     --                                              BPI.20                                                                              21  >2821.5                                                                              >5    --     --                                              BPI.21                                                                              22  >2917  >5    --     --                                              BPI.22                                                                              23  >2821.50                                                                             >5    --     --                                              BPI.23                                                                              24  1330   2.36  >2821.15                                                                             >5                                              BPI.24                                                                              25  655    1.16  >2821.50                                                                             >5                                              BPI.25                                                                              26  >2866.8                                                                              >5    --     --                                              BPI.26                                                                              27  >2852.1                                                                              >5    --     --                                              BPI.27                                                                              28  >2797.8                                                                              >5    --     --                                              BPI.28                                                                              29  >2821.5                                                                              >5    --     --                                              BPI.29                                                                              56  442    1.5   >1469.2                                                                              >5                                              BPI.30                                                                              52  76     0.23  608    1.84                                            BPI.31                                                                              33  938    1.55  --     --                                              BPI.32                                                                              34  614    1.04  --     --                                              BPI.33                                                                              35  575    0.95  --     --                                              BPI.34                                                                              36  916    1.54  --     --                                              BPI.35                                                                              37  263    0.45  --     --                                              BPI.36                                                                             38   1652   2.64  --     --                                              BPI.37                                                                              39  1284   2.14  --     --                                              BPI.38                                                                              40  1698   2.83  --     --                                              BPI.39                                                                              41  316    0.52  --     --                                              BPI.40                                                                              42  1760   2.94  --     --                                              BPI.41                                                                              43  2465   4.03  --     --                                              BPI.42                                                                              44  265    0.44  >3041.3                                                                              >5                                              BPI.43                                                                              45  729    1.21  >3024.8                                                                              >5                                              BPI.44                                                                              46  481    0.8   2983   4.93                                            BPI.45                                                                              31  1302   2.23  >1696.7                                                                              >5                                              BPI.47                                                                              58  98     0.25  577    1.46                                            BPI.48                                                                              59  42     0.1   254    0.61                                            BPI.54                                                                              5   --     --    --     --                                              BPI.55                                                                              61  299    0.75  >1592.2                                                                              >5                                              BPI.56                                                                              47  1387   2.54  --     --                                              BPI.57                                                                              99  514    1.05  --     --                                              BPI.58                                                                              9   1050   2.03  --     --                                              BPI.59                                                                              30  >2312.3                                                                              >5    --     --                                              BPI.60                                                                             32   >2136.5                                                                              >5    --     --                                              BPI.61                                                                              48  >2093.5                                                                              >5    --     --                                              BPI.63                                                                              53  87     0.31  512    1.8                                             BPI.65                                                                              10  895    1.82  --     --                                              oxidized                                                                      BPI.65                                                                              68  1362   2.77  --     --                                              reduced                                                                       BPI.66                                                                              49  >3496.7                                                                              >5    --     --                                              BPI.67                                                                              50  >1901.8                                                                              >5    --     --                                              BPI.69                                                                              60  57     0.21  244    0.88                                            BPI.70                                                                              63  --     --    --     --                                              BPI.71                                                                              64  2297   4.53  --     --                                              BPI.72                                                                              66  >1911.2                                                                              >5    --     --                                              BPI.73                                                                              62  57     0.11  >1810.9                                                                              >5                                              BPI.74                                                                              70  732    2.21  >2148.2                                                                              >5                                              BPI.75                                                                             100  2030.8 4.96  --     --                                              BPI.76                                                                              71  >3906.5                                                                              >5    --     --                                              BPI.77                                                                              72  455    0.85  --     --                                              BPI.79                                                                              73  >2282.9                                                                              >5    --     --                                              BPI.80                                                                              74  655    1.24  --     --                                              BPI.81                                                                              75  284    0.52  >2344.9                                                                              >5                                              BPI.82                                                                              76  171    0.32  >1197.8                                                                              >5                                              BPI.83                                                                              77  155    0.27  >2033.5                                                                              >5                                              BPI.84                                                                              78  12     0.02  >2016.9                                                                              >5                                              BPI.85                                                                              79  227    0.4   >1881.2                                                                              >5                                              BPI.86                                                                              80  1520   2.58  --     --                                              BPI.87                                                                              81  189    0.32  >1535.8                                                                              >5                                              BPI.88                                                                              82  70.32  0.13  540.15 1                                               BPI.89                                                                              84  229.09 0.43  >1882.4                                                                              >5                                              BPI.90                                                                              85  83.11  0.16  1763   3.32                                            BPI.91                                                                              86  >3843.5                                                                              >5    --     --                                              BPI.92                                                                              87  331.8  0.57  --     --                                              BPI.93                                                                              88  212.87 0.76  >980.3 >5                                              BPI.94                                                                              89  922.54 1.59  >922.5 >5                                              BPI.95                                                                              90  330.88 0.6   >1397.6                                                                              >5                                              BPI.96                                                                             101  378.33 0.6   >1397.6                                                                              >5                                              BPI.97                                                                              92  296.58 0.53  --     --                                              BPI.98                                                                              83  >1626.1                                                                              >5    >1626.1                                                                              >5                                              BPI.99                                                                              93  722.9  2.99  >1064.1                                                                              >5                                              BPI.100                                                                             94  407.74 0.73  >2655  >5                                              BPI.101                                                                             95  1329.3 4.79  >1329.3                                                                              >5                                              BPI.102                                                                             96  >2635.6                                                                              >5    >2635.6                                                                              >5                                              BPI.103                                                                            102  165.18 0.31  415.19 0.78                                            BPI.104                                                                            103  385.85 0.64  1376.42                                                                              2.30                                            BPI.105                                                                            427.12                                                                             0.72   >3413.80                                                                            >5                                                     BPI.106                                                                            105  427.12 0.72  >3413.80                                                                             >5                                              BPI.107                                                                            106  384.67 0.68  >2795.70                                                                             >5                                              BPI.108                                                                            107  661.05 1.17  >3219.02                                                                             >5                                              BPI.109                                                                            108  306.80 0.54  >2822.90                                                                             >5                                              BPI.110                                                                            109  812.33 1.44  >2950.15                                                                             >5                                              BPI.111                                                                            110  959.00 1.71  >2808.69                                                                             >5                                              BPI.112                                                                            111  1485.92                                                                              2.84  --     --                                              BPI.113                                                                            112  270.66 0.50  >2950.15                                                                             >5                                              BPI.114                                                                            113  2329.68                                                                              3.10  --     --                                              BPI.116                                                                            114  73.82  0.13  >2788.19                                                                             >5                                              BPI.119                                                                            115  106.70 0.20  536.44 1.02                                            BPI.120                                                                            116  --     --    --     --                                              BPI.121                                                                            117  154.35 0.3   1856.40                                                                              3.55                                            BPI.122                                                                            118  179.89 0.36  2123.57                                                                              4.2                                             BPI.123                                                                            119  247.20 0.43  >2865.02                                                                             >5                                              BPI.124                                                                            120  91.23  0.17  >2580.12                                                                             >5                                              BPI.125                                                                            121  428.85 0.75  >3149.74                                                                             >5                                              BPI.126                                                                            122  1979.97                                                                              3.39  --     --                                              BPI.127                                                                            123  406.01 0.68  --     --                                              BPI.128                                                                            124  2271.14                                                                              3.80  --     --                                              BPI.129                                                                            125  2271.14                                                                              3.80  --     --                                              BPI.130                                                                            126  325.75 0.68  >2903.34                                                                             >5                                              BPI.131                                                                            127  1438.21                                                                              2.48  --     --                                              BPI.132                                                                            128  >2988.50                                                                             >5    --     --                                              BPI.133                                                                            129  2316.59                                                                              3.91  --     --                                              BPI.134                                                                            130  162.5  0.30  580.11 1.05                                            BPI.135                                                                            131  1052.02                                                                              1.74  3321.69                                                                              >5                                              BPI.136                                                                            132  >3030.74                                                                             >5    --     --                                              BPI.137                                                                            133  N.T.   N.T.  N.T.   N.T.                                            BPI.138                                                                            134  64.57  0.11  995.40 1.74                                            BPI.139                                                                            135  1261.37                                                                              2.13  3793.91                                                                              >5                                              BPI.140                                                                            136  84.76  0.26  605.34 1.89                                            BPI.141                                                                            137  >2809.51                                                                             >5    --     --                                              BPI.142                                                                            138  922.21 1.76  --     --                                              BPI.143                                                                            139  >2838.99                                                                             >5    --     --                                              BPI.144                                                                            140  510.02 0.86  --     --                                              BPI.145                                                                            141  N.T.   N.T.  N.T.   N.T.                                            BPI.146                                                                            142  --     --    --     --                                              BPI.147                                                                            143  >2558.17                                                                             >5    --     --                                              BPI.148                                                                            144  >2805.45                                                                             >5    --     --                                              BPI.149                                                                            147  44.00  0.57  391.00 5.00                                            BPI.150                                                                            148  220.00 0.58  >2380.67                                                                             >5                                              BPI.151   N.T.   N.T.  N.T.   N.T.                                            BPI.152   N.T.   N.T.  N.T.   N.T.                                            BPI.153                                                                            149  N.T.   N.T.  N.T.   N.T.                                            BPI.154                                                                            150  197.00 0.55  2977.76                                                                              >5                                              BPI.155                                                                            151  >1795.66                                                                             >5    >1795.66                                                                             >5                                              BPI.156                                                                            152  N.T.   N.T.  N.T.   N.T.                                            BPI.157                                                                            153  N.T.   N.T.  N.T.   N.T.                                            BPI.158                                                                            154  N.T.   N.T.  N.T.   N.T.                                            BPI.159                                                                            155  765.43 2.41  >1589.88                                                                             >5                                              BPI.160                                                                            156  288.78 0.81  >1781.59                                                                             >5                                              BPI.161                                                                            157  1201.79                                                                              2.00  --     --                                              BPI.162                                                                            158  N.T.   N.T.  N.T.   N.T.                                            BPI.163                                                                            159  N.T.   N.T.  N.T.   N.T.                                            BPI.164                                                                            160  N.T.   N.T.  N.T.   N.T.                                            BPI.165                                                                            161  N.T.   N.T.  N.T.   N.T.                                            BPI.166                                                                            162  514.00 0.83  >3078.72                                                                             >5                                              BPI.167                                                                            163  >4585.73                                                                             >5    --     --                                              BPI.168                                                                            164  1460.98                                                                              2.87  >1948.48                                                                             >5                                              BPI.169                                                                            165  4893.83                                                                              >5    > 4974.43                                                                            >5                                              BPI.170                                                                            227  3693.06                                                                              >5    --     --                                              MAP.1*    106    0.82  552.79 4.27                                            MAP.2**   >690.9 >5    >690.9 >5                                              __________________________________________________________________________     .sup.a Amount added to well to achieve a 30 mm.sup.2 hole as determined b     PROBIT analysis as described in Examples 15 and 16.                           .sup.b No detectable activity up to 5 μg/well.                             .sup.c N.T. = not tested                                                      *MAP.1 = β-AlaNα,Nε-[Nα,Nε(BPI.2)Lys]Lys     **MAP.2 =                                                                     β-AlaNα,Nε-[Nα,Nε(BPI.13)Lys]Lys        

EXAMPLE 25 EFFECTS OF CONCURRENT ADMINISTRATION OF BPI PROTEIN PRODUCTAND TETRACYCLINE OR GENTAMICIN ON E. COLI O111:B4

Additional MIC assays were performed to determine the sensitivity of E.coli 0111:B4 (as described in Example 1) to the effects of BPI proteinproducts concurrently administered with the antibiotic tetracycline orwith the antibiotic gentamicin.

For these experiments, organisms were grown overnight at 37° C. in 5 mLof Mueller-Hinton broth. This overnight culture was diluted 1:50 into 5mL of fresh broth and incubated for an additional 3 hours at 37° C. toattain log-phase growth. Bacteria were pelleted for 5 minutes at 1500 ×g and resuspended in fresh broth to give a final concentration of 2×10⁶cells per mL.

rBPI₂₃ and antibiotic (either tetracycline or gentamicin) were dilutedsuch that 100 μl bacterial suspension, 50 μl antibiotic and 50 μldiluted rBPI₂₃, gave concentrations in serial dilutions from 10 μg/mLtetracycline or 2.5 μg/mL gentamicin and from 30 μg/mL rBPI₂₃ with afixed concentration of 10⁶ cells/mL. Incubation was carried out in flatbottom 96 well microliter plates for 18 hours at 37° C., and the plateswere read in an automatic plate reader (Titretek Multiscan) at 590 nm.

A 4-6 fold decrease in absorbance was observed with tetracycline orgentamicin with certain concentrations of BPI protein product. The MICof tetracycline without rBPI₂₃ of 10 μg/mL and was reduced by rBPI₂₃ to5 μg/mL. The MIC of gentamicin without rBPI₂₃ was 0.6 μg/mL and wasreduced by rBPI₂₃ to 0.3 μg/mL.

A partial summary of the data described in the foregoing examples,grouped by general classes of antibiotics, appears below in Table 34 andis displayed as the effects of BPI protein products on the therapeuticeffectiveness of antibiotics for various gram-negative organisms.

                  TABLE 34                                                        ______________________________________                                                   EFFECTS OF BPI PROTEIN PRODUCT                                     ANTIBIOTIC WHEN CONCURRENTLY ADMINISTER-                                      CLASS      ED WITH ANTIBIOTICS WITHIN CLASS                                   ______________________________________                                        β-lactams:                                                                          reversed resistance of Pseudomonas aeruginosa,                     penicillins and                                                                          other Pseudomonas, Xanthamonas, E. coli,                           cephalosporins                                                                           Citrobacter, Klebsiella, Enterobacter,                                        Serratia, Providencia, Acinetobacter                                          increased susceptibility of Pseudomonas                                       aeruginosa, other Pseudomonas, E. coli,                                       Citrobacter, Klebsiella, Enterobacter,                                        Serratia, roteus, Providencia, Morganella,                                    Acinetobacter                                                                 enchanced early bctericidal effect for E. coli,                               Enterobacter in killing curves                                                in vivo synergy shown for treatment of E. coli                                infection in mouse and rabbit models                               β-lactams                                                                           aztreonam:                                                         other than reversed resistance of Pseudomonas aeruginosa,                     penicillins and                                                                          Acinetobacter                                                      cephalosporins:                                                                          increased susceptibility of Acinetobacter                          aztreonam and                                                                            increased susceptibility of Pseudomonas                            imipenem   aeruginosa, Citrobacter, Enterobacter                                         imipenem:                                                                     increased susceptibility of Pseudomonas                                       aeruginosa, Proteus, Providencia,                                             Acinetobacter                                                      aminoglycosides                                                                          reversed resistance of Pseudomonas aeruginosa,                                Xanthamonas, Acinetobacter                                                    increased susceptibility of Pseudomonas                                       aeruginosa, other Pseudomonas, E. coli,                                       Citrobacter, Serratia, Proteus, Providencia,                                  Morganella, Acinetobacter                                                     checkerboard synergy (FIC < 0.5) for E. coli,                                 Salmonella, Klebsiella, Edwardsiella; greater                                 than additive interaction (FIC ≦ 1.0) for                              Pseudomonas aeruginosa, Enterobacter                                          in vivo synergy shown for treatment of E. coli                                infection in mouse model                                           sulfonamides                                                                             reversed resistance of Pseudomonas aeruginosa,                     and        Xanthamonas, Klebsiella, Acinetobacter                             trimethoprim                                                                             increased susceptibility of Enterobacter,                                     Proteus, Acinetobacter                                                        enhanced early bactericidal effect for                                        Klebsiella, Enterobacter in killing curves;                                   slight early enhancement for E. coli                               fluoroquinolones                                                                         reversed resistance of Pseudomonas aeruginosa,                     and quinolones                                                                           Acinetobacter                                                                 increased susceptibility of Pseudomonas                                       aeruginosa, Xanthamonas, Enterobacter,                                        Acinetobacter                                                                 reversed resistance of Klebsiella in antibiotic                               killing curves                                                     polymyxins checkerboard synergy (FIC < 0.5) for                                          Pseudomonas aeruginosa, E. coli, Providencia;                                 additive interaction (FIC ≦ 1.0) for                                   Enterobacter                                                       chloramphenicol                                                                          reversed resistance and increased susceptibility                              for Acinetobacter                                                  ______________________________________                                    

Numerous modifications and variations in the practice of the inventionare expected to occur to those skilled in the art upon consideration ofthe foregoing description of the presently preferred embodimentsthereof. Consequently, the only limitations which should be placed uponthe scope of the present invention are those which appear in theappended claims.

    __________________________________________________________________________    SEQUENCE LISTING                                                              (1) GENERAL INFORMATION:                                                      (iii) NUMBER OF SEQUENCES: 227                                                (2) INFORMATION FOR SEQ ID NO:1:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 29 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                              (D) OTHER INFORMATION: "Domain I"                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                       AlaSerGlnGlnGlyThrAlaAlaLeuGlnLysGluLeuLysArgIle                              151015                                                                        LysIleProAsp TyrSerAspSerPheLysIleLysHis                                      2025                                                                          (2) INFORMATION FOR SEQ ID NO:2:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 30 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- feature                                            (D) OTHER INFORMATION: "BPI.14"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                       GlyThrAlaAlaLeuGlnLysGluLeuLysArgIleLysIleProAsp                              151015                                                                        TyrS erAspSerPheLysIleLysHisLeuGlyLysGlyHis                                   202530                                                                        (2) INFORMATION FOR SEQ ID NO:3:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 22 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE: peptide                                                  (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.4"                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                       LeuGlnLysGluLeuLysArgIleLysIleProAspTyrSerAspSer                              151 015                                                                       PheLysIleLysHisLeu                                                            20                                                                            (2) INFORMATION FOR SEQ ID NO:4:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- feature                                            (D) OTHER INFORMATION: "BPI.1"                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                                       GlnGlnGlyThrAlaAlaLeuGlnLysGluLeuLysArgIleLys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:5:                                               (i) SEQUENCE CHARACTERISTICS:                                                (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.54"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                       GlyThrAlaAlaLeuGlnLysGluLeuLys ArgIleLysIlePro                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:6:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- feature                                            (D) OTHER INFORMATION: "Domain II"                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                                       SerSerGlnIleSerMetValProAsnValGlyLeuLysPheSerIle                              151015                                                                         SerAsnAlaAsnIleLysIleSerGlyLysTrpLysAlaGlnLysArg                             202530                                                                        PheLeuLys                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:7:                                              (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 15 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.2"                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                                       IleLysIleSerGlyLysTrpLysAlaGlnLysArgPheL euLys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:8:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.8"                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                                       LysTrpLysAlaGlnLysArgPheLeuLys                                                1510                                                                          (2) INFORMATION FOR SEQ ID NO:9:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.58"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                                       CysIleLysIleSerGlyLysTrpLysAlaGlnLysArgPheLeuLys                              1 51015                                                                       (2) INFORMATION FOR SEQ ID NO:10:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.65 oxidized"                                      (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                                      CysIleLysIleSerGlyLysTrpLysAlaGlnLysArgPheLeuLys                              151015                                                                        Cys                                                                           (2) INFORMATION FOR SEQ ID NO:11:                                             (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 27 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.3"                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                                      AsnValGlyLeuLysPheSerIleSerAsnAlaAsnIle LysIleSer                             151015                                                                        GlyLysTrpLysAlaGlnLysArgPheLeuLys                                             2025                                                                          (2) INFORMATION FOR SEQ ID NO:12:                                             (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 28 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "Domain III"                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:                                      ValHisValHisIleSerLysSerLysValGlyTrp LeuIleGlnLeu                             151015                                                                        PheHisLysLysIleGluSerAlaLeuArgAsnLys                                          2025                                                                          (2) INFORMATION FOR SEQ ID NO:13:                                              (i) SEQUENCE CHARACTERISTICS:                                                (A) LENGTH: 13 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.11"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:                                      LysSerLysValTrpLeuIleGlnLeuPheH isLysLys                                      1510                                                                          (2) INFORMATION FOR SEQ ID NO:14:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 29 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                              (D) OTHER INFORMATION: "BPI.12"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:                                      SerValHisValHisIleSerLysSerLysValGlyTrpLeuIleGln                              151015                                                                        LeuPheHisLysLysIleGl uSerAlaLeuArgAsnLys                                      2025                                                                          (2) INFORMATION FOR SEQ ID NO:15:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.13"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:                                      LysSerLysValGlyTrpLeuIleGlnLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:16:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                     (B) TYPE: amino acid                                                         (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.15"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:                                      AlaLysIleSerGlyLysTrpLysAlaGlnLysArgPheLeuLys                                 1 51015                                                                       (2) INFORMATION FOR SEQ ID NO:17:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                              (D) OTHER INFORMATION: "BPI.16"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:                                      IleAlaIleSerGlyLysTrpLysAlaGlnLysArgPheLeuLys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:18:                                             (i) SEQUENCE CHARACTERISTICS:                                                 ( A) LENGTH: 15 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.17"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:                                      IleLysAlaSerGlyLysTrpLysAlaGlnLysArgPheLeuLys                                  151015                                                                       (2) INFORMATION FOR SEQ ID NO:19:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                              (D) OTHER INFORMATION: "BPI.18"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:                                      IleLysIleAlaGlyLysTrpLysAlaGlnLysArgPheLeuLys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:20:                                             (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 15 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.19"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:                                      IleLysIleSerAlaLysTrpLysAlaGlnLysArgPhe LeuLys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:21:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 ( A) NAME/KEY: misc.sub.-- feature                                            (D) OTHER INFORMATION: "BPI.20"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:                                      IleLysIleSerGlyAlaTrpLysAlaGlnLysArgPheLeuLys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:22:                                              (i) SEQUENCE CHARACTERISTICS:                                                (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.21"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:                                      IleLysIleSerGlyLysAlaLysAlaGlnL ysArgPheLeuLys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:23:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- feature                                            (D) OTHER INFORMATION: "BPI.22"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:                                      IleLysIleSerGlyLysTrpAlaAlaGlnLysArgPheLeuLys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:24:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.23"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:                                      IleLysIleSerGlyLysTrpLys AlaAlaLysArgPheLeuLys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:25:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                    (ix) FEATURE:                                                                (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.24"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:                                      IleLysIleSerGlyLysTrpLysAlaGlnAlaArgPheLeuLys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:26:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.25"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:                                      IleLysIleSerGlyL ysTrpLysAlaGlnLysAlaPheLeuLys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:27:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.26"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:                                      IleLysIleSerGlyLysTrpLysAlaGlnLysArgAlaLeuLys                                 1510 15                                                                       (2) INFORMATION FOR SEQ ID NO:28:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.27"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:                                      IleLysIle SerGlyLysTrpLysAlaGlnLysArgPheAlaLys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:29:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.28"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:                                      IleLysIleSerGlyLysTrpLysAlaGlnLysArgPheLeuAla                                 1510 15                                                                       (2) INFORMATION FOR SEQ ID NO:30:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.59"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:                                      I leLysIleSerGlyAlaTrpAlaAlaGlnLysArgPheLeuLys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:31:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                         (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.45"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:                                      IleLysIleSerGlyLysTrpLysAlaAlaAlaArgPheLeuLys                                 15 1015                                                                       (2) INFORMATION FOR SEQ ID NO:32:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.60"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:                                      IleAlaIleSerGlyLysTrpLysAlaGlnLysArgPheLeuAla                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:33:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.31"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:                                      AlaSerLysValGlyTrpLeuIleGlnLeuPheHisLysLys                                    15 10                                                                         (2) INFORMATION FOR SEQ ID NO:34:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.32"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:                                      LysA laLysValGlyTrpLeuIleGlnLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:35:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                    (ix) FEATURE:                                                                (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.33"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:                                      LysSerAlaValGlyTrpLeuIleGlnLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:36:                                             ( i) SEQUENCE CHARACTERISTICS:                                                (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.34"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:                                      LysSerLysAlaGlyTrpLeuIleGlnLeuPhe HisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:37:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                              (D) OTHER INFORMATION: "BPI.35"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:                                      LysSerLysValAlaTrpLeuIleGlnLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:38:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    ( B) TYPE: amino acid                                                         (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.36"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:                                      LysSerLysValGlyAlaLeuIleGlnLeuPheHisLysLys                                    15 10                                                                         (2) INFORMATION FOR SEQ ID NO:39:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.37"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:                                       LysSerLysValGlyTrpAlaIleGlnLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:40:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.38"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:                                      LysSerLysValGlyTrpLeuAlaGlnLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:41:                                              (i) SEQUENCE CHARACTERISTICS:                                                (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.39"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:                                      LysSerLysValGlyTrpLeuIleAlaLe uPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:42:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                              (D) OTHER INFORMATION: "BPI.40"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:                                      LysSerLysValGlyTrpLeuIleGlnAlaPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:43:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                     (B) TYPE: amino acid                                                         (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.41"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:                                      LysSerLysValGlyTrpLeuIleGlnLeuAlaHisLysLys                                    1 510                                                                         (2) INFORMATION FOR SEQ ID NO:44:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.42"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:                                       LysSerLysValGlyTrpLeuIleGlnLeuPheAlaLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:45:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (i i) MOLECULE TYPE: peptide                                                  (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.43"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:                                      LysSerLysValGlyTrpLeuIleGlnLeuPheHisAlaLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:46:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.44"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:                                      LysSerLysValGlyTrpLeuIleG lnLeuPheHisLysAla                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:47:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.56"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:                                      IleLysIleSerGlyLysTrpLysAlaLysGlnArgPheLeuLys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:48:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.61"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:                                      IleLysIleSerGlyLysPheLysAlaGlnLysArg PheLeuLys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:49:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- feature                                            (D) OTHER INFORMATION: "BPI.66"                                               (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 7                                                               (D) OTHER INFORMATION: /label=D- Trp                                          /note="The amino acid at position 7 is                                        D- tryptophan"                                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:                                      IleLysIleSerGlyLys TrpLysAlaGlnLysArgPheLeuLys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:50:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.67"                                               (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6..8                                                            (D) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 7 is                                           beta-1- naphthyl-substituted"                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:                                      I leLysIleSerGlyLysAlaLysAlaGlnLysArgPheLeuLys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:51:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                         (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.9"                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:                                      LysArgPheLeuLysLysTrpLysAlaGlnLysArgPheLeuLys                                 15 1015                                                                       (2) INFORMATION FOR SEQ ID NO:52:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.30"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:                                      LysTrpLysAlaGlnLysArgPheLeuLysLysSerLysValGlyTrp                              151015                                                                        LeuIleGlnLeuPheHisLysLys                                                      20                                                                            (2) INFORMATION FOR SEQ ID NO:53:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 29 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.63"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:                                      IleLysIleSerGly LysTrpLysAlaGlnLysArgPheLeuLysLys                             151015                                                                        SerLysValGlyTrpLeuIleGlnLeuPheHisLysLys                                       20 25                                                                         (2) INFORMATION FOR SEQ ID NO:54:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.7"                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:                                      LysTrpL ysAlaGlnLysArgPheLeuLysLysTrpLysAlaGlnLys                             151015                                                                        ArgPheLeuLys                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO:55:                                             (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 25 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.10.1"                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:                                      LysArgPheLeuLysLysTrpLysAlaGlnLysArgPheLe uLysLys                             151015                                                                        TrpLysAlaGlnLysArgPheLeuLys                                                   2025                                                                          (2) INFORMATION FOR SEQ ID NO:56:                                             (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 28 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.29"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:                                      LysSerLysValGlyTrpLeuIleGlnLeuPheHisLysLysLys Ser                             151015                                                                        LysValGlyTrpLeuIleGlnLeuPheHisLysLys                                          2025                                                                          (2) INFORMATION FOR SEQ ID NO:57:                                             (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 20 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.46"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:                                      LysTrpLysAlaAlaAlaArgPheLeuLysLysTrpLys AlaGlnLys                             151015                                                                        ArgPheLeuLys                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO:58:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20 amino acids                                                    (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                         (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.47"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:                                      LysTrpLysAlaGlnLysArgPheLeuLysLysTrpLysAlaAlaAla                              15 1015                                                                       ArgPheLeuLys                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO:59:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- feature                                            (D) OTHER INFORMATION: "BPI.48"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:                                      LysTrpLysAlaAlaAlaArgPheLeuLysLysTrpLysAlaAlaAla                              151015                                                                        Arg PheLeuLys                                                                 20                                                                            (2) INFORMATION FOR SEQ ID NO:60:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 30 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.69"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60:                                      LysTrpLysAlaAlaAlaArgPheLeuLysLysTrpLysAlaAlaAla                              151015                                                                        ArgPheLeuLysLysTrpLysAlaAlaAlaArgPheL euLys                                   202530                                                                        (2) INFORMATION FOR SEQ ID NO:61:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.55"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61:                                      GlyTrpLeuIleGlnLeuPheHisLysLysIleGluSerAlaLeuArg                              151015                                                                        AsnLysMetAs nSer                                                              20                                                                            (2) INFORMATION FOR SEQ ID NO:62:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.73"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62:                                      IleLysIleSerGlyLysTrpLysAlaGlnPheArgPheLeuLys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:63:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                         (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.70"                                               (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 8..10                                                           (D) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 7 is                                            beta-3- pyridyl-substituted"                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:63:                                      IleLysIleSerGlyLysAlaLysAlaGlnLysArgPheLeuLys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:64:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.71"                                               (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 13..15                                                          (D) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 13 is                                          beta-3- pyridyl-substituted"                                                  (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64:                                      IleLysIleSerGlyLysTrpLysAlaGlnLysArgAlaLeuLys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:65:                                             (i ) SEQUENCE CHARACTERISTICS:                                                (A) LENGTH: 26 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.10.2"                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:65:                                      GlnLysArgPheLeuLysLysTrpLysAlaGln LysArgPheLeuLys                             151015                                                                        LysTrpLysAlaGlnLysArgPheLeuLys                                                2025                                                                          (2) INFORMATION FOR SEQ ID NO:66:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.72"                                               (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1..3                                                            (D) OTHER INFORMATION: /label=D- alanine                                      /note="The position 1 and position 2 alanine                                  residues are both D-alanine"                                                  (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66:                                      AlaAlaIleLysIleSerGlyLysTrpLysAlaGlnLysArgPheLeu                              1510 15                                                                       Lys                                                                           (2) INFORMATION FOR SEQ ID NO:67:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 22 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.5"                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:67:                                      Val HisValHisIleSerLysSerLysValGlyTrpLeuIleGlnLeu                             151015                                                                        PheHisLysLysIleGlu                                                            20                                                                            (2) INFORMATION FOR SEQ ID NO:68:                                              (i) SEQUENCE CHARACTERISTICS:                                                (A) LENGTH: 17 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.65 reduced"                                       (ix) FEATURE:                                                                 (A) NAME/KEY: Disulfide-bond                                                  (B) LOCATION: 1..17                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:68:                                      CysIleLysIleSerGlyLysTrpLysAlaGlnLysArgPheLeuLys                              151015                                                                        Cys                                                                           (2) INFORMATION FOR SEQ ID NO:69:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 487 amino acids                                                    (B) TYPE: amino acid                                                         (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: protein                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "rBPI"                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69:                                      MetArgGluAsnMetAlaArgGlyProCysAsnAlaProArgTrpVal                              -31-3 0-25-20                                                                 SerLeuMetValLeuValAlaIleGlyThrAlaValThrAlaAlaVal                              -15-10-51                                                                     AsnProGlyValV alValArgIleSerGlnLysGlyLeuAspTyrAla                             51015                                                                         SerGlnGlnGlyThrAlaAlaLeuGlnLysGluLeuLysArgIleLys                              20 2530                                                                       IleProAspTyrSerAspSerPheLysIleLysHisLeuGlyLysGly                              354045                                                                        HisTyrSerPheTyrSerMetAspIleArgGluPheGlnLe uProSer                             50556065                                                                      SerGlnIleSerMetValProAsnValGlyLeuLysPheSerIleSer                              7075 80                                                                       AsnAlaAsnIleLysIleSerGlyLysTrpLysAlaGlnLysArgPhe                              859095                                                                        LeuLysMetSerGlyAsnPheAspLeuSerIleGluGlyMetSerIle                               100105110                                                                    SerAlaAspLeuLysLeuGlySerAsnProThrSerGlyLysProThr                              115120125                                                                     IleThrCysSerSerCysSer SerHisIleAsnSerValHisValHis                             130135140145                                                                  IleSerLysSerLysValGlyTrpLeuIleGlnLeuPheHisLysLys                              150 155160                                                                    IleGluSerAlaLeuArgAsnLysMetAsnSerGlnValCysGluLys                              165170175                                                                     ValThrAsnSerValSerSerLysLeuGlnP roTyrPheGlnThrLeu                             180185190                                                                     ProValMetThrLysIleAspSerValAlaGlyIleAsnTyrGlyLeu                              195200205                                                                     Val AlaProProAlaThrThrAlaGluThrLeuAspValGlnMetLys                             210215220225                                                                  GlyGluPheTyrSerGluAsnHisHisAsnProProProPheAlaPro                               230235240                                                                    ProValMetGluPheProAlaAlaHisAspArgMetValTyrLeuGly                              245250255                                                                     LeuSerAspTyr PhePheAsnThrAlaGlyLeuValTyrGlnGluAla                             260265270                                                                     GlyValLeuLysMetThrLeuArgAspAspMetIleProLysGluSer                              275280 285                                                                    LysPheArgLeuThrThrLysPhePheGlyThrPheLeuProGluVal                              290295300305                                                                  AlaLysLysPheProAsnMetLysIleGlnIle HisValSerAlaSer                             310315320                                                                     ThrProProHisLeuSerValGlnProThrGlyLeuThrPheTyrPro                              325330 335                                                                    AlaValAspValGlnAlaPheAlaValLeuProAsnSerSerLeuAla                              340345350                                                                     SerLeuPheLeuIleGlyMetHisThrThrGlySerMetGluValSer                               355360365                                                                    AlaGluSerAsnArgLeuValGlyGluLeuLysLeuAspArgLeuLeu                              370375380385                                                                  LeuGluLeuLysHis SerAsnIleGlyProPheProValGluLeuLeu                             390395400                                                                     GlnAspIleMetAsnTyrIleValProIleLeuValLeuProArgVal                              405 410415                                                                    AsnGluLysLeuGlnLysGlyPheProLeuProThrProAlaArgVal                              420425430                                                                     GlnLeuTyrAsnValValLeuGlnProHisGln AsnPheLeuLeuPhe                             435440445                                                                     GlyAlaAspValValTyrLys                                                         450455                                                                        (2) INFORMATION FOR SEQ ID NO:70:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24 amino acids                                                    (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                         (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.74"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:70:                                      LysSerLysValGlyTrpLeuIleGlnLeuPheHisLysLysLysTrp                              15 1015                                                                       LysAlaGlnLysArgPheLeuLys                                                      20                                                                            (2) INFORMATION FOR SEQ ID NO:71:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                    (ix) FEATURE:                                                                (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.76"                                               (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 10..12                                                          (D) OTHER INFORMATION: /label=D- Phe                                          /note="The amino acid at position 11 is                                       D- phenylalanine"                                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:71:                                      Ile LysIleSerGlyLysTrpLysAlaGlnPheArgPheLeuLys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:72:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                         (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.77"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:72:                                      IleLysIleSerGlyLysTrpLysAlaGlnTrpArgPheLeuLys                                 15 1015                                                                       (2) INFORMATION FOR SEQ ID NO:73:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.79"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:73:                                      IleLysIleSerGlyLysTrpLysAlaLysLysArgPheLeuLys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:74:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                         (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.80"                                               (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 10..12                                                          (D) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 11 is                                           beta-1- naphthyl-substituted"                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:74:                                      IleLysIleSerGlyLysTrpLysAlaGlnAlaArgPheLeuLys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:75:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.81"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:75:                                      IleLysIleSerGlyLysTrpLysAlaPheLysArgPheLeuLys                                  151015                                                                       (2) INFORMATION FOR SEQ ID NO:76:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                              (D) OTHER INFORMATION: "BPI.82"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:76:                                      LysSerLysValGlyTrpLeuIleGlnLeuTrpHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:77:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                     (B) TYPE: amino acid                                                         (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.83"                                               (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 10..12                                                          (D) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 6 is                                            beta-1- naphthyl-substituted"                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:77:                                      LysSerLysValGlyAlaLysIleGlnLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:78:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B ) TYPE: amino acid                                                         (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.84"                                               (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6..8                                                            (D) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 7 is                                            beta-1- naphthyl-substituted"                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78:                                      IleLysIleSerGlyLysAlaLysAlaGlnPheArgPheLeuLys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:79:                                             (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 14 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.85"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:79:                                      LysSerLysValLeuTrpLeuIleGlnLeuPheHisLysLys                                     1510                                                                         (2) INFORMATION FOR SEQ ID NO:80:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.86"                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:80:                                     LysSerLysValGlyTrpLeuIleLeuLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:81:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                         (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.87"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:81:                                      LysSerLysValGlyTrpLeuIleGlnLeuPheLeuLysLys                                    15 10                                                                         (2) INFORMATION FOR SEQ ID NO:82:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.88"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:82:                                      IleLysIleSer GlyLysTrpLysAlaPhePheArgPheLeuLys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:83:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE: peptide                                                  (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.98"                                               (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 2                                                               (D) OTHER INFORMATION: /label=Substituted-Trp                                 /note="The alanine at position 2 is                                           beta-1- naphthyl-substituted"                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:83:                                       LysTrpLysAlaGlnPheArgPheLeuLysLysSerLysValGlyTrp                             151015                                                                        LeuIlePheLeuPheHisLysLys                                                      20                                                                            (2) INFORMATION FOR SEQ ID NO:84:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.89"                                               (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6..8                                                            (D) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 7 is                                           beta-1- naphthyl-substituted"                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:84:                                      IleLysIleSerGlyLysAlaLysAlaPheLysArgPheLeuLys                                 1510 15                                                                       (2) INFORMATION FOR SEQ ID NO:85:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.90"                                               (ix) FEATURE:                                                                 ( A) NAME/KEY: Modified-site                                                  (B) LOCATION: 6..8                                                            (D) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 7 is                                           beta-1- naphthyl-substituted"                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:85:                                      IleLysIleSerGlyLysAlaLysAlaPhePheArgPheLeuLys                                 15 1015                                                                       (2) INFORMATION FOR SEQ ID NO:86:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.91"                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:86:                                     LysSerLysValGlyTrpLeuIlePheLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:87:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                         (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.92"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:87:                                      LysSerLysValGlyTrpLeuIleLysLeuPheHisLysLys                                    15 10                                                                         (2) INFORMATION FOR SEQ ID NO:88:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 29 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.93"                                               (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                    (B) LOCATION: 6..8                                                           (D) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 7 is                                           beta-1- naphthyl-substituted"                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:88:                                      IleLysIleSerGlyLysAlaLysAlaGlnPheArgPheLeuLysLys                              15 1015                                                                       SerLysValGlyTrpLeuIleGlnLeuPheHisLysLys                                       2025                                                                          (2) INFORMATION FOR SEQ ID NO:89:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                         (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.94"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:89:                                      LysSerLysValGlyTrpLeuIleGlnLeuPhePheLysLys                                    15 10                                                                         (2) INFORMATION FOR SEQ ID NO:90:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.95"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:90:                                      LysSer LysValPheTrpLeuIleGlnLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:91:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                    (ix) FEATURE:                                                                (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.96"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:91:                                      LysSerLysValGlyTrpLeuIleGlnLeuPheHisLysPhe                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:92:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.97"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:92:                                      LysSerLysValLysTrpLeuIleGlnLeuPheHi sLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:93:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 30 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                              (D) OTHER INFORMATION: "BPI.99"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:93:                                      LysTrpLysAlaGlnTrpArgPheLeuLysLysTrpLysAlaGlnTrp                              151015                                                                        ArgPheLeuLysLysTrpLys AlaGlnTrpArgPheLeuLys                                   202530                                                                        (2) INFORMATION FOR SEQ ID NO:94:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix ) FEATURE:                                                                (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.100"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:94:                                      LysSerLysValLysTrpLeuIleLysLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:95:                                             (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 28 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.101"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:95:                                      LysSerLysValLysTrpLeuIleLysLeuPhePheL ysPheLysSer                             151015                                                                        LysValLysTrpLeuIleLysLeuPhePheLysPhe                                          2025                                                                          (2) INFORMATION FOR SEQ ID NO:96:                                              (i) SEQUENCE CHARACTERISTICS:                                                (A) LENGTH: 24 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.102"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:96:                                      LysTrpLysAlaGlnPheArgPheLeuLysLy sSerLysValGlyTrp                             151015                                                                        LeuIleLeuLeuPheHisLysLys                                                      20                                                                            (2) INFORMATION FOR SEQ ID NO:97:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 1443 base pairs                                                    (B) TYPE: nucleic acid                                                       (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA                                                       (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: 1..1443                                                         (ix) FEATURE:                                                                 (A) NAME/KEY: mat.sub.-- peptide                                              (B) LOCATION: 76..1443                                                        (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "rLBP"                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:97:                                      ATGGGGGCCTTGGCCAGAGCCCTGCCGTCCATACTGCTGGCATTGCTG48                            MetGlyAlaLeuAlaArgAlaLeuProSerIleLeuLeuAlaLeuLeu                              -25 -20-15-10                                                                 CTTACGTCCACCCCAGAGGCTCTGGGTGCCAACCCCGGCTTGGTCGCC96                            LeuThrSerThrProGluAlaLeuGlyAlaAsnProGlyLeuValAla                               -515                                                                         AGGATCACCGACAAGGGACTGCAGTATGCGGCCCAGGAGGGGCTATTG144                           ArgIleThrAspLysGlyLeuGlnTyrAlaAlaGlnGluGlyLeuLeu                               101520                                                                       GCTCTGCAGAGTGAGCTGCTCAGGATCACGCTGCCTGACTTCACCGGG192                           AlaLeuGlnSerGluLeuLeuArgIleThrLeuProAspPheThrGly                               253035                                                                       GACTTGAGGATCCCCCACGTCGGCCGTGGGCGCTATGAGTTCCACAGC240                           AspLeuArgIleProHisValGlyArgGlyArgTyrGluPheHisSer                              40 455055                                                                     CTGAACATCCACAGCTGTGAGCTGCTTCACTCTGCGCTGAGGCCTGTC288                           LeuAsnIleHisSerCysGluLeuLeuHisSerAlaLeuArgProVal                               606570                                                                       CCTGGCCAGGGCCTGAGTCTCAGCATCTCCGACTCCTCCATCCGGGTC336                           ProGlyGlnGlyLeuSerLeuSerIleSerAspSerSerIleArgVal                               758085                                                                       CAGGGCAGGTGGAAGGTGCGCAAGTCATTCTTCAAACTACAGGGCTCC384                           GlnGlyArgTrpLysValArgLysSerPhePheLysLeuGlnGlySer                               9095100                                                                      TTTGATGTCAGTGTCAAGGGCATCAGCATTTCGGTCAACCTCCTGTTG432                           PheAspValSerValLysGlyIleSerIleSerValAsnLeuLeuLeu                               105110115                                                                    GGCAGCGAGTCCTCCGGGAGGCCCACAGTTACTGCCTCCAGCTGCAGC480                           GlySerGluSerSerGlyArgProThrValThrAlaSerSerCysSer                              120 125130135                                                                 AGTGACATCGCTGACGTGGAGGTGGACATGTCGGGAGACTTGGGGTGG528                           SerAspIleAlaAspValGluValAspMetSerGlyAspLeuGlyTrp                               140145150                                                                    CTGTTGAACCTCTTCCACAACCAGATTGAGTCCAAGTTCCAGAAAGTA576                           LeuLeuAsnLeuPheHisAsnGlnIleGluSerLysPheGlnLysVal                               155160165                                                                    CTGGAGAGCAGGATTTGCGAAATGATCCAGAAATCGGTGTCCTCCGAT624                           LeuGluSerArgIleCysGluMetIleGlnLysSerValSerSerAsp                               170175180                                                                    CTACAGCCTTATCTCCAAACTCTGCCAGTTACAACAGAGATTGACAGT672                           LeuGlnProTyrLeuGlnThrLeuProValThrThrGluIleAspSer                               185190195                                                                    TTCGCCGACATTGATTATAGCTTAGTGGAAGCCCCTCGGGCAACAGCC720                           PheAlaAspIleAspTyrSerLeuValGluAlaProArgAlaThrAla                              200 205210215                                                                 CAGATGCTGGAGGTGATGTTTAAGGGTGAAATCTTTCATCGTAACCAC768                           GlnMetLeuGluValMetPheLysGlyGluIlePheHisArgAsnHis                               220225230                                                                    CGTTCTCCAGTTACCCTCCTTGCTGCAGTCATGAGCCTTCCTGAGGAA816                           ArgSerProValThrLeuLeuAlaAlaValMetSerLeuProGluGlu                               235240245                                                                    CACAACAAAATGGTCTACTTTGCCATCTCGGATTATGTCTTCAACACG864                           HisAsnLysMetValTyrPheAlaIleSerAspTyrValPheAsnThr                               250255260                                                                    GCCAGCCTGGTTTATCATGAGGAAGGATATCTGAACTTCTCCATCACA912                           AlaSerLeuValTyrHisGluGluGlyTyrLeuAsnPheSerIleThr                               265270275                                                                    GATGAGATGATACCGCCTGACTCTAATATCCGACTGACCACCAAGTCC960                           AspGluMetIleProProAspSerAsnIleArgLeuThrThrLysSer                              280 285290295                                                                 TTCCGACCCTTCGTCCCACGGTTAGCCAGGCTCTACCCCAACATGAAC1008                          PheArgProPheValProArgLeuAlaArgLeuTyrProAsnMetAsn                               300305310                                                                    CTGGAACTCCAGGGATCAGTGCCCTCTGCTCCGCTCCTGAACTTCAGC1056                          LeuGluLeuGlnGlySerValProSerAlaProLeuLeuAsnPheSer                               315320325                                                                    CCTGGGAATCTGTCTGTGGACCCCTATATGGAGATAGATGCCTTTGTG1104                          ProGlyAsnLeuSerValAspProTyrMetGluIleAspAlaPheVal                               330335340                                                                    CTCCTGCCCAGCTCCAGCAAGGAGCCTGTCTTCCGGCTCAGTGTGGCC1152                          LeuLeuProSerSerSerLysGluProValPheArgLeuSerValAla                               345350355                                                                    ACTAATGTGTCCGCCACCTTGACCTTCAATACCAGCAAGATCACTGGG1200                          ThrAsnValSerAlaThrLeuThrPheAsnThrSerLysIleThrGly                              360 365370375                                                                 TTCCTGAAGCCAGGAAAGGTAAAAGTGGAACTGAAAGAATCCAAAGTT1248                          PheLeuLysProGlyLysValLysValGluLeuLysGluSerLysVal                               380385390                                                                    GGACTATTCAATGCAGAGCTGTTGGAAGCGCTCCTCAACTATTACATC1296                          GlyLeuPheAsnAlaGluLeuLeuGluAlaLeuLeuAsnTyrTyrIle                               395400405                                                                    CTTAACACCTTCTACCCCAAGTTCAATGATAAGTTGGCCGAAGGCTTC1344                          LeuAsnThrPheTyrProLysPheAsnAspLysLeuAlaGluGlyPhe                               410415420                                                                    CCCCTTCCTCTGCTGAAGCGTGTTCAGCTCTACGACCTTGGGCTGCAG1392                          ProLeuProLeuLeuLysArgValGlnLeuTyrAspLeuGlyLeuGln                               425430435                                                                    ATCCATAAGGACTTCCTGTTCTTGGGTGCCAATGTCCAATACATGAGA1440                          IleHisLysAspPheLeuPheLeuGlyAlaAsnValGlnTyrMetArg                              440 445450455                                                                 GTT1443                                                                       Val                                                                           (2) INFORMATION FOR SEQ ID NO:98:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 481 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: protein                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "rLBP"                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:98:                                      MetGlyAlaLeuAlaArgAlaLeuProSerIleLeuLeuAlaLeuLeu                              -25-20 -15-10                                                                 LeuThrSerThrProGluAlaLeuGlyAlaAsnProGlyLeuValAla                              -515                                                                          ArgIleThrAspLysGlyLeuG lnTyrAlaAlaGlnGluGlyLeuLeu                             101520                                                                        AlaLeuGlnSerGluLeuLeuArgIleThrLeuProAspPheThrGly                              2530 35                                                                       AspLeuArgIleProHisValGlyArgGlyArgTyrGluPheHisSer                              40455055                                                                      LeuAsnIleHisSerCysGluLeuLeuHisSerAlaLeuArgPr oVal                             606570                                                                        ProGlyGlnGlyLeuSerLeuSerIleSerAspSerSerIleArgVal                              758085                                                                        Gln GlyArgTrpLysValArgLysSerPhePheLysLeuGlnGlySer                             9095100                                                                       PheAspValSerValLysGlyIleSerIleSerValAsnLeuLeuLeu                              105 110115                                                                    GlySerGluSerSerGlyArgProThrValThrAlaSerSerCysSer                              120125130135                                                                  SerAspIleAlaAspValGluValA spMetSerGlyAspLeuGlyTrp                             140145150                                                                     LeuLeuAsnLeuPheHisAsnGlnIleGluSerLysPheGlnLysVal                              155160 165                                                                    LeuGluSerArgIleCysGluMetIleGlnLysSerValSerSerAsp                              170175180                                                                     LeuGlnProTyrLeuGlnThrLeuProValThrThrGluIleAs pSer                             185190195                                                                     PheAlaAspIleAspTyrSerLeuValGluAlaProArgAlaThrAla                              200205210215                                                                  GlnMet LeuGluValMetPheLysGlyGluIlePheHisArgAsnHis                             220225230                                                                     ArgSerProValThrLeuLeuAlaAlaValMetSerLeuProGluGlu                              2 35240245                                                                    HisAsnLysMetValTyrPheAlaIleSerAspTyrValPheAsnThr                              250255260                                                                     AlaSerLeuValTyrHisGluGluG lyTyrLeuAsnPheSerIleThr                             265270275                                                                     AspGluMetIleProProAspSerAsnIleArgLeuThrThrLysSer                              280285290 295                                                                 PheArgProPheValProArgLeuAlaArgLeuTyrProAsnMetAsn                              300305310                                                                     LeuGluLeuGlnGlySerValProSerAlaProLeuLeuA snPheSer                             315320325                                                                     ProGlyAsnLeuSerValAspProTyrMetGluIleAspAlaPheVal                              330335340                                                                     LeuLeu ProSerSerSerLysGluProValPheArgLeuSerValAla                             345350355                                                                     ThrAsnValSerAlaThrLeuThrPheAsnThrSerLysIleThrGly                              360365 370375                                                                 PheLeuLysProGlyLysValLysValGluLeuLysGluSerLysVal                              380385390                                                                     GlyLeuPheAsnAlaGluLeu LeuGluAlaLeuLeuAsnTyrTyrIle                             395400405                                                                     LeuAsnThrPheTyrProLysPheAsnAspLysLeuAlaGluGlyPhe                              410415 420                                                                    ProLeuProLeuLeuLysArgValGlnLeuTyrAspLeuGlyLeuGln                              425430435                                                                     IleHisLysAspPheLeuPheLeuGlyAlaAsnValGlnTyrMetArg                               440445450455                                                                 Val                                                                           (2) INFORMATION FOR SEQ ID NO:99:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.57"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:99:                                      CysIleLysIleSerGlyLysTrpLysAlaGlnLysArgProLeuCys                              151015                                                                        (2) INFORMATION FOR SEQ ID NO:100:                                             (i) SEQUENCE CHARACTERISTICS:                                                (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.75"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:100:                                     IleLysLysArgAlaIleSerPheLeuGly LysLysTrpGlnLys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:101:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- feature                                            (D) OTHER INFORMATION: "BPI.282"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:101:                                     LysTrpLysAlaPhePheArgPheLeuLysLysTrpLysAlaPhePhe                              151015                                                                         ArgPheLeuLys                                                                 20                                                                            (2) INFORMATION FOR SEQ ID NO:102:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.103"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:102:                                    IleLysIleSerGlyLysTrpLysAlaTrpLysArgPheLeuLysLys                              151015                                                                        (2) INFORMATION FOR SEQ ID NO:103:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                     (B) TYPE: amino acid                                                         (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.104"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:103:                                     LysSerLysValGlyTrpLeuIleSerLeuPheHisLysLys                                    1 510                                                                         (2) INFORMATION FOR SEQ ID NO:104:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.105"                                              (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 13                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 13 is beta-1-                                  naphthyl- substituted."                                                       (xi) SEQUENCE DESCRIPTION: SEQ ID NO:104:                                     IleLysIleSerGlyLysTrpLysAlaTrpLysArgAlaLeuLysLys                              1 51015                                                                       (2) INFORMATION FOR SEQ ID NO:105:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                              (D) OTHER INFORMATION: "BPI.106"                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:105:                                     LysSerLysValGlyTrpLeuIleThrLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:106:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B ) TYPE: amino acid                                                         (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.107"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:106:                                     LysSerLysValGlyTrpLeuIleGlnLeuPheTrpLysLys                                    15 10                                                                         (2) INFORMATION FOR SEQ ID NO:107:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.108"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:107:                                     L ysSerLysValGlyTrpLeuIleGlnLeuPheHisLysTrp                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:108:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.109"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 11                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 11 is beta-1-                                  naphthyl- substituted."                                                       (xi) SEQUENCE DESCRIPTION: SEQ ID NO:108:                                     Ly sSerLysValGlyTrpLeuIleGlnLeuAlaHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:109:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.110"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 12                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 12 is beta-1-                                  naphthyl- substituted."                                                       (xi) SEQUENCE DESCRIPTION: SEQ ID NO:109:                                     Lys SerLysValGlyTrpLeuIleGlnLeuPheAlaLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:110:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                    (ix) FEATURE:                                                                (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.111"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 14                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 14 is beta-1-                                  naphthyl- substituted."                                                       (xi) SEQUENCE DESCRIPTION: SEQ ID NO:110:                                     Lys SerLysValGlyTrpLeuIleGlnLeuPheHisLysAla                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:111:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                    (ix) FEATURE:                                                                (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.112"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 7                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 7 is beta-1-                                   naphthyl- substituted."                                                       (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 11                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 11 is beta-1-                                  naphthyl- substituted."                                                       (xi) SEQUENCE DESCRIPTION: SEQ ID NO:111:                                     IleLysIleSerGlyLysAlaLysAlaGlnAlaArgPheLeuLys                                 15 1015                                                                       (2) INFORMATION FOR SEQ ID NO:112:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.113"                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:112:                                    LysSerLysValGlyTrpLeuIleGlnPhePheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:113:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D ) TOPOLOGY: linear                                                         (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.114"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:113:                                     LysTrpGlnLeuArgSerLysGlyLysIleLysIlePheLysAla                                 15 1015                                                                       (2) INFORMATION FOR SEQ ID NO:114:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.116"                                              (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 6 is beta-1-                                   naphthyl- substituted."                                                       (xi) SEQUENCE DESCRIPTION: SEQ ID NO:114:                                     LysSerLysValLysAlaLeuIleGlnLeuPheHisLysLys                                    1 510                                                                         (2) INFORMATION FOR SEQ ID NO:115:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.119"                                              (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 7                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 7 is beta-1-                                   naphthyl- substituted."                                                       (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 10                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 10 is beta-1-                                   naphthyl- substituted."                                                      (xi) SEQUENCE DESCRIPTION: SEQ ID NO:115:                                     IleLysIleSerGlyLysAlaLysAlaAlaLysArgPheLeuLys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:116:                                            (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 15 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.120"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:116:                                     IleLysIleSerGlyLysTrpLysAlaGlnLysArgLysLeu Lys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:117:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.121"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 10                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 10 is beta-1-                                  naphthyl- substituted."                                                       (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 11                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                /note="The alanine at position 11 is beta-1-                                  naphthyl- substituted."                                                       (xi) SEQUENCE DESCRIPTION: SEQ ID NO:117:                                     IleLysIleSerGlyLysTrpLysAlaAlaAlaArgPheLeuLys                                 1510 15                                                                       (2) INFORMATION FOR SEQ ID NO:118:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.122"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                    (B) LOCATION: 7                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 7 is beta-1-                                   naphthyl- substituted."                                                       (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 10                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 10 is beta-1-                                  naphthyl- substituted."                                                       (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 11                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 11 is beta-1-                                  naphthyl- substituted."                                                       (xi) SEQUENCE DESCRIPTION: SEQ ID NO:118:                                     IleLysIleSerGlyLysAlaLysAlaAlaAlaArgPheLeu Lys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:119:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.123"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 9                                                               (C) OTHER INFORMATION: /label=Substituted-Phe                                 /note="The phenylalanine at position 9 is                                     p-amino- substituted."                                                        (xi) SEQUENCE DESCRIPTION: SEQ ID NO:119:                                     LysSerLysValGlyTrpLeuIlePh eLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:120:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.124"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:120:                                     LysSerLysValLysTrpLeuIleGlnLeuTrpHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:121:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                     (B) TYPE: amino acid                                                         (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.125"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:121:                                     LysSerLysValGlyTrpLeuIleTyrLeuPheHisLysLys                                    1 510                                                                         (2) INFORMATION FOR SEQ ID NO:122:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.126"                                              (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=D- Trp                                          /note="The amino acid at position 6 is                                        D- tryptophan."                                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:122:                                     LysSerLysValGlyTrpLeuIleGlnLeuPheHisLysLys                                    1 510                                                                         (2) INFORMATION FOR SEQ ID NO:123:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.127"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:123:                                     LysSerLysValGlyPheLeuIleGlnLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:124:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE: peptide                                                  (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.128"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=D- Phe                                          /note="The amino acid at position 6 is                                        D- phenylalanine."                                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:124:                                     LysSerLysValGlyPheLeuIleGlnLeuProHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:125:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                           (ii) MOLECULE TYPE: peptide                                                  (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.129"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 6 is                                           D-1-beta-1- naphthyl-                                                         substituted."                                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:125:                                     LysSerLysValGlyAlaLeuIleGlnLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:126:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                         (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.130"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 6 is                                           2-beta-1- naphthyl-                                                            substituted."                                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:126:                                     LysSerLysValGlyAlaLeuIleGlnLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:127:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                     (B) TYPE: amino acid                                                         (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.131"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 6 is                                            D-2-beta-1- naphthyl-                                                        substituted."                                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:127:                                     LysSerLysValGlyAlaLeuIleGlnLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:128:                                            (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 14 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.132"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                  /note="The alanine at position 6 is                                          pyridyl- substituted."                                                        (xi) SEQUENCE DESCRIPTION: SEQ ID NO:128:                                     LysSerLysValGlyAlaLeuIleGlnLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:129:                                            (i) SEQUENCE CHARACTERISTICS:                                                 ( A) LENGTH: 14 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.133"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Phe                                  /note="The phenylalanine at position 6 is                                    para-amino-                                                                   substituted."                                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:129:                                     LysSerLysValGlyPheLeuIleGlnLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:130:                                            (i ) SEQUENCE CHARACTERISTICS:                                                (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.134"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 5                                                               (C) OTHER INFORMATION: /label=Substituted-Phe                                 /note="The phenylalanine at position 5 is                                     para-amino- substituted."                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:130:                                     LysSerLysValPheTrpLeuIleGlnLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:131:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.135"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:131:                                     LysSerLysValGlyLysLeuIleGlnLeuProHi sLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:132:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                              (D) OTHER INFORMATION: "BPI.136"                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:132:                                     IleLysIleSerGlyLysTrpLysAlaGlnGluArgPheLeuLys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:133:                                            (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 16 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.137"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:133:                                     CysLysSerLysValGlyTrpLeuIleGlnLeuPheHisLysLys Cys                             151015                                                                        (2) INFORMATION FOR SEQ ID NO:134:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.138"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:134:                                     LysSerLysValLysPheLeuIleGlnLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:135:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                     (B) TYPE: amino acid                                                         (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.139"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:135:                                     LysSerLysValGlyTyrLeuIleGlnLeuPheHisLysLys                                    1 510                                                                         (2) INFORMATION FOR SEQ ID NO:136:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.140"                                              (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 1                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 1 is                                           beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 2                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 2 is                                            beta-1- naphthyl-substituted."                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:136:                                     AlaAlaArgPheLeuLysPhe                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:137:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                    (ix) FEATURE:                                                                (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.141"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:137:                                     IleLysIleSerGlyLysTrpLysAlaGlnLysArgTrpLeuLys                                 1510 15                                                                       (2) INFORMATION FOR SEQ ID NO:138:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.142"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:138:                                     LysSerLysValGl yTrpLeuIleGlnTrpPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:139:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- feature                                            (D) OTHER INFORMATION: "BPI.143"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 10                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 10 is                                          beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:139:                                     LysSerLysValGly TrpLeuIleGlnAlaPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:140:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- feature                                            (D) OTHER INFORMATION: "BPI.144"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 6 is                                           cyclohexyl- substituted."                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:140:                                     LysSerLysValGlyAl aLeuIleGlnLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:141:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- feature                                            (D) OTHER INFORMATION: "BPI.145"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:141:                                     LysTrpLysAlaAlaAlaArgPheLeuLysLysSerLysValGlyTrp                              151015                                                                        Leu IleGlnLeuPheHisLysLys                                                     20                                                                            (2) INFORMATION FOR SEQ ID NO:142:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.146"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 12                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 12 is                                          beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 14                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                  /note="The alanine at position 14 is                                         beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:142:                                     LysSerLysValGlyTrpLeuIleGlnLeuPheAlaLysAla                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:143:                                            (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 15 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.147"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:143:                                     IleLysIleSerGlyLysTrpLysAlaGluLysLysPheLeu Lys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:144:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub. -- feature                                            (D) OTHER INFORMATION: "BPI.148"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 6 is                                           beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 12                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                /note="The alanine at position 12 is                                          beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:144:                                     LysSerLysValGlyAlaLeuIleGlnLeuPheAlaLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:145:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 1813 base pairs                                                   (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: cDNA                                                      (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: 31..1491                                                        (ix) FEATURE:                                                                 (A) NAME/KEY: mat.sub.-- peptide                                              (B ) LOCATION: 124..1491                                                      (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "rBPI"                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:145:                                     CAGGCCTTGAGGTTTTGGCAGCTCTGGAGGATGAGAGAGAACATGGCCAGGGGC54                      MetArgGluA snMetAlaArgGly                                                     -31-30-25                                                                     CCTTGCAACGCGCCGAGATGGGTGTCCCTGATGGTGCTCGTCGCCATA102                           ProCysAsnAlaProArgTrpValSerL euMetValLeuValAlaIle                             -20-15-10                                                                     GGCACCGCCGTGACAGCGGCCGTCAACCCTGGCGTCGTGGTCAGGATC150                           GlyThrAlaValThrAlaAlaValAs nProGlyValValValArgIle                             -515                                                                          TCCCAGAAGGGCCTGGACTACGCCAGCCAGCAGGGGACGGCCGCTCTG198                           SerGlnLysGlyLeuAspTyrAlaSerGlnG lnGlyThrAlaAlaLeu                             10152025                                                                      CAGAAGGAGCTGAAGAGGATCAAGATTCCTGACTACTCAGACAGCTTT246                           GlnLysGluLeuLysArgIleLysI leProAspTyrSerAspSerPhe                             303540                                                                        AAGATCAAGCATCTTGGGAAGGGGCATTATAGCTTCTACAGCATGGAC294                           LysIleLysHisLeuGlyLysG lyHisTyrSerPheTyrSerMetAsp                             455055                                                                        ATCCGTGAATTCCAGCTTCCCAGTTCCCAGATAAGCATGGTGCCCAAT342                           IleArgGluPheGlnLeuProS erSerGlnIleSerMetValProAsn                             606570                                                                        GTGGGCCTTAAGTTCTCCATCAGCAACGCCAATATCAAGATCAGCGGG390                           ValGlyLeuLysPheSerIleSerA snAlaAsnIleLysIleSerGly                             758085                                                                        AAATGGAAGGCACAAAAGAGATTCTTAAAAATGAGCGGCAATTTTGAC438                           LysTrpLysAlaGlnLysArgPheLeuLysM etSerGlyAsnPheAsp                             9095100105                                                                    CTGAGCATAGAAGGCATGTCCATTTCGGCTGATCTGAAGCTGGGCAGT486                           LeuSerIleGluGlyMetSerIleS erAlaAspLeuLysLeuGlySer                             110115120                                                                     AACCCCACGTCAGGCAAGCCCACCATCACCTGCTCCAGCTGCAGCAGC534                           AsnProThrSerGlyLysProT hrIleThrCysSerSerCysSerSer                             125130135                                                                     CACATCAACAGTGTCCACGTGCACATCTCAAAGAGCAAAGTCGGGTGG582                           HisIleAsnSerValHisValH isIleSerLysSerLysValGlyTrp                             140145150                                                                     CTGATCCAACTCTTCCACAAAAAAATTGAGTCTGCGCTTCGAAACAAG630                           LeuIleGlnLeuPheHisLysLysI leGluSerAlaLeuArgAsnLys                             155160165                                                                     ATGAACAGCCAGGTCTGCGAGAAAGTGACCAATTCTGTATCCTCCAAG678                           MetAsnSerGlnValCysGluLysValThrA snSerValSerSerLys                             170175180185                                                                  CTGCAACCTTATTTCCAGACTCTGCCAGTAATGACCAAAATAGATTCT726                           LeuGlnProTyrPheGlnThrLeuP roValMetThrLysIleAspSer                             190195200                                                                     GTGGCTGGAATCAACTATGGTCTGGTGGCACCTCCAGCAACCACGGCT774                           ValAlaGlyIleAsnTyrGlyL euValAlaProProAlaThrThrAla                             205210215                                                                     GAGACCCTGGATGTACAGATGAAGGGGGAGTTTTACAGTGAGAACCAC822                           GluThrLeuAspValGlnMet LysGlyGluPheTyrSerGluAsnHis                             220225230                                                                     CACAATCCACCTCCCTTTGCTCCACCAGTGATGGAGTTTCCCGCTGCC870                           HisAsnProProProPheAlaPro ProValMetGluPheProAlaAla                             235240245                                                                     CATGACCGCATGGTATACCTGGGCCTCTCAGACTACTTCTTCAACACA918                           HisAspArgMetValTyrLeuGlyLeuSer AspTyrPhePheAsnThr                             250255260265                                                                  GCCGGGCTTGTATACCAAGAGGCTGGGGTCTTGAAGATGACCCTTAGA966                           AlaGlyLeuValTyrGlnGluAla GlyValLeuLysMetThrLeuArg                             270275280                                                                     GATGACATGATTCCAAAGGAGTCCAAATTTCGACTGACAACCAAGTTC1014                          AspAspMetIleProLysGlu SerLysPheArgLeuThrThrLysPhe                             285290295                                                                     TTTGGAACCTTCCTACCTGAGGTGGCCAAGAAGTTTCCCAACATGAAG1062                          PheGlyThrPheLeuProGlu ValAlaLysLysPheProAsnMetLys                             300305310                                                                     ATACAGATCCATGTCTCAGCCTCCACCCCGCCACACCTGTCTGTGCAG1110                          IleGlnIleHisValSerAlaSer ThrProProHisLeuSerValGln                             315320325                                                                     CCCACCGGCCTTACCTTCTACCCTGCCGTGGATGTCCAGGCCTTTGCC1158                          ProThrGlyLeuThrPheTyrProAlaVal AspValGlnAlaPheAla                             330335340345                                                                  GTCCTCCCCAACTCCTCCCTGGCTTCCCTCTTCCTGATTGGCATGCAC1206                          ValLeuProAsnSerSerLeuAla SerLeuPheLeuIleGlyMetHis                             350355360                                                                     ACAACTGGTTCCATGGAGGTCAGCGCCGAGTCCAACAGGCTTGTTGGA1254                          ThrThrGlySerMetGluVal SerAlaGluSerAsnArgLeuValGly                             365370375                                                                     GAGCTCAAGCTGGATAGGCTGCTCCTGGAACTGAAGCACTCAAATATT1302                          GluLeuLysLeuAspArgLeu LeuLeuGluLeuLysHisSerAsnIle                             380385390                                                                     GGCCCCTTCCCGGTTGAATTGCTGCAGGATATCATGAACTACATTGTA1350                          GlyProPheProValGluLeuLeu GlnAspIleMetAsnTyrIleVal                             395400405                                                                     CCCATTCTTGTGCTGCCCAGGGTTAACGAGAAACTACAGAAAGGCTTC1398                          ProIleLeuValLeuProArgValAsnGlu LysLeuGlnLysGlyPhe                             410415420425                                                                  CCTCTCCCGACGCCGGCCAGAGTCCAGCTCTACAACGTAGTGCTTCAG1446                          ProLeuProThrProAlaArgVal GlnLeuTyrAsnValValLeuGln                             430435440                                                                     CCTCACCAGAACTTCCTGCTGTTCGGTGCAGACGTTGTCTATAAA1491                             ProHisGlnAsnPheLeuLeu PheGlyAlaAspValValTyrLys                                445450455                                                                     TGAAGGCACCAGGGGTGCCGGGGGCTGTCAGCCGCACCTGTTCCTGATGGGCTGTGGGGC1551              ACCGGCTGCCTTTCCCCAGGGAATCCTC TCCAGATCTTAACCAAGAGCCCCTTGCAAACT1611             TCTTCGACTCAGATTCAGAAATGATCTAAACACGAGGAAACATTATTCATTGGAAAAGTG1671              CATGGTGTGTATTTTAGGGATTATGAGCTTCTTTCAAGGGCTAAGGCTGCAGAGATATTT1731              CC TCCAGGAATCGTGTTTCAATTGTAACCAAGAAATTTCCATTTGTGCTTCATGAAAAAA1791             AACTTCTGGTTTTTTTCATGTG1813                                                    (2) INFORMATION FOR SEQ ID NO:146:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 487 amino acids                                                    (B) TYPE: amino acid                                                         (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: protein                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:146:                                     MetArgGluAsnMetAlaArgGlyProCysAsnAlaProArgTrpVal                              -31-30-25-20                                                                  SerLeuMetV alLeuValAlaIleGlyThrAlaValThrAlaAlaVal                             -15-10-51                                                                     AsnProGlyValValValArgIleSerGlnLysGlyLeuAspTyrAla                               51015                                                                        SerGlnGlnGlyThrAlaAlaLeuGlnLysGluLeuLysArgIleLys                              202530                                                                        IleProAspTyrSerAspSerPhe LysIleLysHisLeuGlyLysGly                             354045                                                                        HisTyrSerPheTyrSerMetAspIleArgGluPheGlnLeuProSer                              505560 65                                                                     SerGlnIleSerMetValProAsnValGlyLeuLysPheSerIleSer                              707580                                                                        AsnAlaAsnIleLysIleSerGlyLysTrpLysAlaGln LysArgPhe                             859095                                                                        LeuLysMetSerGlyAsnPheAspLeuSerIleGluGlyMetSerIle                              100105110                                                                     SerA laAspLeuLysLeuGlySerAsnProThrSerGlyLysProThr                             115120125                                                                     IleThrCysSerSerCysSerSerHisIleAsnSerValHisValHis                              13013 5140145                                                                 IleSerLysSerLysValGlyTrpLeuIleGlnLeuPheHisLysLys                              150155160                                                                     IleGluSerAlaLeuArgAs nLysMetAsnSerGlnValCysGluLys                             165170175                                                                     ValThrAsnSerValSerSerLysLeuGlnProTyrPheGlnThrLeu                              180185 190                                                                    ProValMetThrLysIleAspSerValAlaGlyIleAsnTyrGlyLeu                              195200205                                                                     ValAlaProProAlaThrThrAlaGluThrLeuAspValGlnMetLys                              210215220225                                                                  GlyGluPheTyrSerGluAsnHisHisAsnProProProPheAlaPro                              230235240                                                                     P roValMetGluPheProAlaAlaHisAspArgMetValTyrLeuGly                             245250255                                                                     LeuSerAspTyrPhePheAsnThrAlaGlyLeuValTyrGlnGluAla                              26 0265270                                                                    GlyValLeuLysMetThrLeuArgAspAspMetIleProLysGluSer                              275280285                                                                     LysPheArgLeuThrThrLysPhePheG lyThrPheLeuProGluVal                             290295300305                                                                  AlaLysLysPheProAsnMetLysIleGlnIleHisValSerAlaSer                              31031 5320                                                                    ThrProProHisLeuSerValGlnProThrGlyLeuThrPheTyrPro                              325330335                                                                     AlaValAspValGlnAlaPheAlaValLeuProAsnSe rSerLeuAla                             340345350                                                                     SerLeuPheLeuIleGlyMetHisThrThrGlySerMetGluValSer                              355360365                                                                     AlaGluSer AsnArgLeuValGlyGluLeuLysLeuAspArgLeuLeu                             370375380385                                                                  LeuGluLeuLysHisSerAsnIleGlyProPheProValGluLeuLeu                               390395400                                                                    GlnAspIleMetAsnTyrIleValProIleLeuValLeuProArgVal                              405410415                                                                     AsnGluLysLeuGlnLysG lyPheProLeuProThrProAlaArgVal                             420425430                                                                     GlnLeuTyrAsnValValLeuGlnProHisGlnAsnPheLeuLeuPhe                              435440 445                                                                    GlyAlaAspValValTyrLys                                                         450455                                                                        (2) INFORMATION FOR SEQ ID NO:147:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.149"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:147:                                     LysTrpLysValPheLysLysIleGluLysLysSerLysValGlyTrp                              151015                                                                        LeuIleGlnLeu PheHisLysLys                                                     20                                                                            (2) INFORMATION FOR SEQ ID NO:148:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.150"                                              ( xi) SEQUENCE DESCRIPTION: SEQ ID NO:148:                                    LysTrpAlaPheAlaLysLysGlnLysLysArgLeuLysArgGlnTrp                              151015                                                                        LeuLysLysPhe                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO:149:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 30 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.153"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:149:                                     LysTrpLysAlaGlnLysArg PheLeuLysLysTrpLysAlaGlnLys                             151015                                                                        ArgPheLeuLysLysTrpLysAlaGlnLysArgPheLeuLys                                    20 2530                                                                       (2) INFORMATION FOR SEQ ID NO:150:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.154"                                              (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 5                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 5 is                                                          beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 6 is                                                           beta-1- naphthyl-substituted."                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:150:                                     LysTrpLysAlaAlaAlaArgPheLeuLysLysTrpLysAlaGlnLys                              151015                                                                        ArgPheLeuLys                                                                   20                                                                           (2) INFORMATION FOR SEQ ID NO:151:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.155"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                    (B) LOCATION: 15                                                             (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 15 is                                                         beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 16                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 16 is                                                         beta-1- naphthyl-substituted."                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:151:                                    LysTrpLysAlaGlnLysArgPheLeuLysLysTrpLysAlaAlaAla                              151015                                                                        ArgPheLeuLys                                                                  20                                                                            (2 ) INFORMATION FOR SEQ ID NO:152:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.156"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 5                                                                (C) OTHER INFORMATION: /label=Substituted-Ala                                /note="Position 5 is                                                          beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 6 is                                                          beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 15                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 15 is                                                         beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 16                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 16 is                                                          beta-1- naphthyl-substituted."                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:152:                                     LysTrpLysAlaAlaAlaArgPheLeuLysLysTrpLysAlaAlaAla                              151015                                                                        ArgPheLeuLys                                                                   20                                                                           (2) INFORMATION FOR SEQ ID NO:153:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 30 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.157"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                    (B) LOCATION: 5                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 5 is                                                          beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 6 is                                                          beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 15                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 15 is                                                         beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 16                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 16 is                                                          beta-1- naphthyl-substituted."                                               (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 25                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 25 is                                                         beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 26                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                  /note="Position 26 is                                                        beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:153:                                     LysTrpLysAlaAlaAlaArgPheLeuLysLysTrpLysAlaAlaAla                              151015                                                                         ArgPheLeuLysLysTrpLysAlaAlaAlaArgPheLeuLys                                   202530                                                                        (2) INFORMATION FOR SEQ ID NO:154:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 29 amino acids                                                    (B) TYPE: amino acid                                                           (D) TOPOLOGY: linear                                                         (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.158"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 10                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 10 is                                                         beta-1- naphthyl-substituted."                                                ( ix) FEATURE:                                                                (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 11                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 11 is                                                         beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:154:                                     IleLysIleSerGlyLysTrpLysAlaAlaAlaArgPheLeuLysLys                               151015                                                                       SerLysValGlyTrpLeuIleGlnLeuPheHisLysLys                                       2025                                                                          (2) INFORMATION FOR SEQ ID NO:155:                                            (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 24 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.159"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 2                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                  /note="Position 2 is                                                         beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 6 is                                                          beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:155:                                     LysAlaLysAlaGlnAlaArgPh eLeuLysLysSerLysValGlyTrp                             151015                                                                        LeuIleGlnLeuTrpHisLysLys                                                      20                                                                            (2) INFORMATION FOR SEQ ID NO:156:                                            (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 20 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.160"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 2                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                  /note="Position 2 is                                                         beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 6 is                                                          beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 12                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                /note="Position 12 is                                                         beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 16                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 16 is                                                         beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:156:                                     Lys AlaLysAlaGlnAlaArgPheLeuLysLysAlaLysAlaGlnAla                             151015                                                                        ArgPheLeuLys                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO:157:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.161"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:157:                                     LysSerLysValLysAlaLeuIleGlnLeuPheHis LysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:158:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             ( D) OTHER INFORMATION: "BPI.162"                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:158:                                     LysTrpLysAlaGlnTrpArgPheLeuLysLysSerLysValGlyTrp                              151015                                                                        LeuIleGlnLeuPheHisLysL ys                                                     20                                                                            (2) INFORMATION FOR SEQ ID NO:159:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.163"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:159:                                      LysTrpLysAlaGlnTrpArgPheLeuLysLysTrpLysAlaGlnTrp                             151015                                                                        ArgPheLeuLys                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO:160:                                             (i) SEQUENCE CHARACTERISTICS:                                                (A) LENGTH: 20 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.164"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 5                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 5 is                                                          beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 15                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 15 is                                                         beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:160:                                     LysTrpLysA laAlaLysArgPheLeuLysLysTrpLysAlaAlaLys                             151015                                                                        ArgPheLeuLys                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO:161:                                            (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 20 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.165"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 2                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                  /note="Position 2 is                                                         beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 12                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 12 is                                                         beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:161:                                     LysAlaLysAlaGlnPheArgPh eLeuLysLysAlaLysAlaGlnPhe                             151015                                                                        ArgPheLeuLys                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO:162:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                     (B) TYPE: amino acid                                                         (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.166"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:162:                                     LysSerLysValGlyValLeuIleGlnLeuPheHisLysLys                                    1 510                                                                         (2) INFORMATION FOR SEQ ID NO:163:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.167"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:163:                                      LysTrpLysAlaGlnLysArgPhe                                                     15                                                                            (2) INFORMATION FOR SEQ ID NO:164:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: circular                                                        (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                              (D) OTHER INFORMATION: "BPI.168"                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:164:                                     CysLysTrpLysAlaGlnLysArgPheLeuLysMetSerCys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:165:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino acids                                                     (B) TYPE: amino acid                                                         (D) TOPOLOGY: circular                                                        (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.169"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:165:                                     CysLysTrpLysAlaGlnLysArgPheCys                                                15 10                                                                         (2) INFORMATION FOR SEQ ID NO:166:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.221"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                    (B) LOCATION: 13                                                             (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 13 is                                                         beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:166:                                     IleLysIleSerGlyLysTrpLysAlaGlnLysArgAlaLeuLys                                 15 1015                                                                       (2) INFORMATION FOR SEQ ID NO:167:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.222"                                              (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 6 is                                                          beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 14                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 14 is                                                          beta-1- naphthyl-substituted."                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:167:                                     LysSerLysValGlyAlaLeuIleGlnLeuPheHisLysAla                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:168:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.223"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 6 is                                                           beta-1- naphthyl-substituted."                                               (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 10                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 10 is                                                         beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:168:                                     LysSerLysValGlyAlaLeuIleGlnAlaPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:169:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.224"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 6 is                                                          beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 9                                                               (C) OTHER INFORMATION: /label=Substituted-Phe                                  /note="Position 9 is                                                         para-amino- substituted."                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:169:                                     LysSerLysValGlyAlaLeuIlePheLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:170:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.225"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 6 is                                                          beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 5                                                               (C) OTHER INFORMATION: /label=Substituted-Phe                                 /note="Position 5 is                                                          para-amino- substituted."                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:170:                                     LysSerLysValPheAlaLeuIleGlnLe uPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:171:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                              (D) OTHER INFORMATION: "BPI.226"                                             (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 6 is                                                          beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:171:                                     LysSerLysValGlyAlaLeuIleGlnLeuTrp HisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:172:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                              (D) OTHER INFORMATION: "BPI.227"                                             (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 10                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 10 is                                                         beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 14                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                  /note="Position 14 is                                                        beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:172:                                     LysSerLysValGlyTrpLeuIleGlnAlaPheHisLysAla                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:173:                                            (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 14 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.228"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 9                                                               (C) OTHER INFORMATION: /label=Substituted-Phe                                  /note="Position 9 is                                                         para-amino- substituted."                                                     (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 14                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 14 is                                                         beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:173:                                     LysSerLysValGlyTrpL euIlePheLeuPheHisLysAla                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:174:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- feature                                            (D) OTHER INFORMATION: "BPI.229"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 5                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 5 is                                                          para-amino- substituted."                                                     (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 14                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                /note="Position 14 is                                                         beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:174:                                     LysSerLysValPheTrpLeuIleGlnLeuPheHisLysAla                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:175:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.230"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 14                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                /note="Position 14 is                                                         beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:175:                                     LysSerLysValGlyTrpLeuIleGlnLeuTrpHisLysAla                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:176:                                             (i) SEQUENCE CHARACTERISTICS:                                                (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.231"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 10                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 10 is                                                         beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 12                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 12 is                                                         beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:176:                                     LysSerLys ValGlyTrpLeuIleGlnAlaPheAlaLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:177:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.232"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 9                                                               (C) OTHER INFORMATION: /label=Substituted-Phe                                 /note="Position 9 is                                                          para-amino- substituted."                                                     (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                    (B) LOCATION: 12                                                             (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 12 is                                                         beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:177:                                     LysSerLysValGlyTrpLeuIlePheLeuPheAlaLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:178:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.233"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 5                                                               (C) OTHER INFORMATION: /label=Substituted-Phe                                 /note="Position 5 is                                                          para-amino- substituted."                                                     (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 12                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 12 is                                                         beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:178:                                      LysSerLysValPheTrpLeuIleGlnLeuPheAlaLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:179:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          ( ii) MOLECULE TYPE: peptide                                                  (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.234"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 12                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 12 is                                                         beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:179:                                      LysSerLysValGlyTrpLeuIleGlnLeuTrpAlaLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:180:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.235"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 9                                                               (C) OTHER INFORMATION: /label=Substituted-Phe                                 /note="Position 9 is                                                          para-amino- substituted."                                                     (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 10                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 10 is                                                         beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:180:                                     LysSerLysValGlyTrpLeuIlePheAlaPheHisLysLys                                    15 10                                                                         (2) INFORMATION FOR SEQ ID NO:181:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.236"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                    (B) LOCATION: 5                                                              (C) OTHER INFORMATION: /label=Substituted-Phe                                 /note="Position 5 is                                                          para-amino- substituted."                                                     (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 10                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 10 is                                                         beta-1- naphthyl-substituted."                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:181:                                    LysSerLysValPheTrpLeuIleGlnAlaPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:182:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          ( D) TOPOLOGY: linear                                                         (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.237"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 10                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 10 is                                                         beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:182:                                     LysSerLysValGlyTrpLeuIleGlnAlaTrpHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:183:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.238"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 5                                                               (C) OTHER INFORMATION: /label=Substituted-Phe                                 /note="Position 5 is                                                          para-amino- substituted."                                                     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 9                                                               (C) OTHER INFORMATION: /label=Substituted-Phe                                 /note="Position 9 is                                                          para-amino- substituted."                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:183:                                     LysSerLysValPheTrpLeuIlePheLeuPheHisLysLys                                    1 510                                                                         (2) INFORMATION FOR SEQ ID NO:184:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.239"                                              (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 9                                                               (C) OTHER INFORMATION: /label=Substituted-Phe                                 /note="Position 9 is                                                          para-amino- substituted."                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:184:                                     LysSerLysValGlyTrpLeuIlePheLeuTrpHisLysLys                                    15 10                                                                         (2) INFORMATION FOR SEQ ID NO:185:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.240"                                              (ix) FEATURE:                                                                 ( A) NAME/KEY: Modified-site                                                  (B) LOCATION: 5                                                               (C) OTHER INFORMATION: /label=Substituted-Phe                                 /note="Position 5 is                                                          para-amino- substituted."                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:185:                                     LysSerLysValPheTrpLeuIleGlnLeuTrpHisLysLys                                    15 10                                                                         (2) INFORMATION FOR SEQ ID NO:186:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.247"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 2                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 2 is                                                          beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 6 is                                                          beta-1- naphthyl-substituted."                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:186:                                    LysAlaLysAlaGlnAlaArgPheLeuLysLysSerLysValGlyTrp                              151015                                                                        LeuIleLeuLeuPheHisLysLys                                                       20                                                                           (2) INFORMATION FOR SEQ ID NO:187:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.245"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:187:                                     LysTrp LysAlaGlnPheArgPheLeuLysLysSerLysValGlyTrp                             151015                                                                        LeuIleGlnLeuTrpHisLysLys                                                      20                                                                            (2) INFORMATION FOR SEQ ID NO:188:                                             (i) SEQUENCE CHARACTERISTICS:                                                (A) LENGTH: 24 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.246"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 16                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                /note="Position 16 is                                                         D-beta-2- naphthyl-substituted."                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:188:                                     LysTrpLysAlaGlnPheArgPheLeuLysLysSerLysValGlyAla                              1510 15                                                                       LeuIleGlnLeuPheHisLysLys                                                      20                                                                            (2) INFORMATION FOR SEQ ID NO:189:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.248"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 2                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 2 is                                                          beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               ( C) OTHER INFORMATION: /label=Substituted-Ala                                /note="Position 6 is                                                          beta-1- naphthyl-substituted."                                                (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 16                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 16 is                                                         D-beta-2- naphthyl-substituted."                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:189:                                     LysAlaL ysAlaGlnAlaArgPheLeuLysLysSerLysValGlyAla                             151015                                                                        LeuIleGlnLeuPheHisLysLys                                                      20                                                                            (2) INFORMATION FOR SEQ ID NO:190:                                             (i) SEQUENCE CHARACTERISTICS:                                                (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.242"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C ) OTHER INFORMATION: /label=Substituted-Ala                                /note="Position 6 is                                                          D-beta-2- naphthyl-substituted."                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:190:                                     LysSerLysValGlyAlaLeuIleLeuLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:191:                                            ( i) SEQUENCE CHARACTERISTICS:                                                (A) LENGTH: 28 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.272"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:191:                                     LysSerLysValGlyTrpLeuIleLeuLeuPhe HisLysLysLysSer                             151015                                                                        LysValGlyTrpLeuIleLeuLeuPheHisLysLys                                          2025                                                                          (2) INFORMATION FOR SEQ ID NO:192:                                             (i) SEQUENCE CHARACTERISTICS:                                                (A) LENGTH: 28 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.275"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:192:                                     LysSerLysValGlyTrpLeuIlePhe LeuPheHisLysLysLysSer                             151015                                                                        LysValGlyTrpLeuIlePheLeuPheHisLysLys                                          2025                                                                          (2) INFORMATION FOR SEQ ID NO:193:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 28 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.270"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:193:                                     LysSerLysValGlyTrpLeuI leLeuLeuPheHisLysLysLysSer                             151015                                                                        LysValGlyTrpLeuIleGlnLeuPheHisLysLys                                          2025                                                                          (2) INFORMATION FOR SEQ ID NO:194:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 28 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.271"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:194:                                     LysSerLysValGlyTr pLeuIleGlnLeuPheHisLysLysLysSer                             151015                                                                        LysValGlyTrpLeuIleLeuLeuPheHisLysLys                                          20 25                                                                         (2) INFORMATION FOR SEQ ID NO:195:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 28 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.273"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:195:                                     LysSerLysVal GlyTrpLeuIlePheLeuPheHisLysLysLysSer                             151015                                                                        LysValGlyTrpLeuIleGlnLeuPheHisLysLys                                          20 25                                                                         (2) INFORMATION FOR SEQ ID NO:196:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 28 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.274"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:196:                                     LysSer LysValGlyTrpLeuIleGlnLeuPheHisLysLysLysSer                             151015                                                                        LysValGlyTrpLeuIlePheLeuPheHisLysLys                                          20 25                                                                         (2) INFORMATION FOR SEQ ID NO:197:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.276"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:197:                                     L ysTrpLysAlaGlnPheArgPheLeuLysLysSerLysValGlyTrp                             151015                                                                        LeuIlePheLeuPheHisLysLys                                                      20                                                                            (2) INFORMATION FOR SEQ ID NO:198:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.241"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:198:                                     LysSerLysValGlyTrpLeuIl eLeuLeuTrpHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:199:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.243"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 6 is                                                          D-beta-2- naphthyl-substituted."                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:199:                                     LysSerLysValGlyAlaLeuIleGln LeuTrpHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:200:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.244"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="Position 6 is                                                          D-beta-2- naphthyl-substituted."                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:200:                                     LysSerLysValGlyAlaLeuIleLeuLeu TrpHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:201:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                              (D) OTHER INFORMATION: "BPI.249"                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:201:                                     LysSerLysValGlyGlyLeuIleGlnLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:202:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                     (B) TYPE: amino acid                                                         (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.250"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:202:                                     LysSerLysValGlyLeuLeuIleGlnLeuPheHisLysLys                                    1 510                                                                         (2) INFORMATION FOR SEQ ID NO:203:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.251"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:203:                                      LysSerLysValGlyIleLeuIleGlnLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:204:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.252"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /label=D- Ala                                          /note="The amino acid at position 6 is                                        D-alanine"                                                                    (xi) SEQUENCE DESCRIPTION: SEQ ID NO:204:                                      LysSerLysValGlyAlaLeuIleGlnLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:205:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.253"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /label=D- Val                                          /note="The amino acid at position 6 is                                        D-valine"                                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:205:                                      LysSerLysValGlyValLeuIleGlnLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:206:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.254"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /label=beta-Ala                                        /note="The amino acid at position 6 is                                        beta- alanine"                                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:206:                                      LysSerLysValGlyAlaLeuIleGlnLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:207:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.255"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /label=delta-aba                                       /note="The amino acid at position 6 is                                        delta- aminobutyric acid"                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:207:                                      LysSerLysValGlyXaaLeuIleGlnLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:208:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.256"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /label=gaba                                            /note="The amino acid at position 6 is                                        gamma- aminobutyric acid"                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:208:                                      LysSerLysValGlyXaaLeuIleGlnLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:209:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.257"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /label=d- methyl-A                                     /note="The amino acid at position 6 is                                        delta-Methyl- alanine"                                                        (xi) SEQUENCE DESCRIPTION: SEQ ID NO:209:                                      LysSerLysValGlyAlaLeuIleGlnLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:210:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.258"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /label=t- butyl-G                                      /note="The amino acid at position 6 is                                        tert-butyl- glycine"                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:210:                                      LysSerLysValGlyGlyLeuIleGlnLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:211:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.259"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /label=N- methyl-G                                     /note="The amino acid at position 6 is                                        N-Methyl- glycine"                                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:211:                                      LysSerLysValGlyGlyLeuIleGlnLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:212:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.260"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /label=N- methyl-V                                     /note="The amino acid at position 6 is                                        N-Methyl- valine"                                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:212:                                      LysSerLysValGlyValLeuIleGlnLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:213:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.261"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /label=N- methyl-L                                     /note="The amino acid at position 6 is                                        N-Methyl- leucine"                                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:213:                                      LysSerLysValGlyLeuLeuIleGlnLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:214:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.262"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:214:                                     LysSerLysValGlyTrpLeuIleAsnLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:215:                                             (i) SEQUENCE CHARACTERISTICS:                                                (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.263"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:215:                                     LysSerLysValGlyTrpLeuIleGluLe uPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:216:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                              (D) OTHER INFORMATION: "BPI.264"                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:216:                                     LysSerLysValGlyTrpLeuIleAspLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:217:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                     (B) TYPE: amino acid                                                         (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.265"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:217:                                     LysSerLysValGlyTrpLeuIleLysLeuPheHisLysLys                                    1 510                                                                         (2) INFORMATION FOR SEQ ID NO:218:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.266"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:218:                                      LysSerLysValLysValLeuIleGlnLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:219:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (i i) MOLECULE TYPE: peptide                                                  (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.267"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:219:                                     LysSerLysValLysTrpAlaIleGlnLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:220:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.268"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:220:                                     LysSerLysValGlyValAlaIleG lnLeuPheHisLysLys                                   1510                                                                          (2) INFORMATION FOR SEQ ID NO:221:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.269"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:221:                                     LysSerLysValLysValAlaIleGlnLeuPheHisLysLys                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:222:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 24 amino acids                                                     (B) TYPE: amino acid                                                         (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.277"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 2                                                               (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 2 is                                           beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:222:                                     LysAlaLysAlaGlnPheArgPheLeuLysLysSerLysValGlyTrp                              151015                                                                        LeuIleLeuLeu PheHisLysLys                                                     20                                                                            (2) INFORMATION FOR SEQ ID NO:223:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.278"                                              ( xi) SEQUENCE DESCRIPTION: SEQ ID NO:223:                                    IleLysIleSerGlyLysTrpLysAlaAlaTrpArgPheLeuLys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:224:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                     (B) TYPE: amino acid                                                         (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.279"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 10                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 10 is                                           beta-1- naphthyl-substituted."                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:224:                                     IleLysIleSerGlyLysTrpLysAlaAlaPheArgPheLeuLys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:225:                                            (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 15 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.280"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:225:                                     IleLysIleSerGlyLysTrpLysAlaAlaPheArgPheLeu Lys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:226:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.281"                                              (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 10                                                              (C) OTHER INFORMATION: /label=Substituted-Ala                                 /note="The alanine at position 10 is                                          beta-1- naphthyl-substituted."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:226:                                     IleLysIleSerGlyLysTrpLysAl aAlaAlaArgPheLeuLys                                151015                                                                        (2) INFORMATION FOR SEQ ID NO:227:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (i x) FEATURE:                                                                (A) NAME/KEY: misc.sub.-- feature                                             (D) OTHER INFORMATION: "BPI.170"                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:227:                                     LysTrpLysAlaGlnLysArgPheLeuLysMetSer                                          1510                                                                      

What is claimed is:
 1. In a method for enhancing the effect of antibiotic treatment of a patient infected with gram-negative bacteria by concurrently administering bactericidal/permeability-increasing (BPI) protein and an antibiotic, the improvement comprising concurrently administering BPI protein product and polymyxin B in the treatment of a patient infected with a gram-negative bacteria selected from the group consisting of Escherichia, Providencia, and Pseudomonas species.
 2. In a method for enhancing the effect of antibiotic treatment of a patient infected with gram-negative bacteria by concurrently administering bactericidal/permeability-increasing (BPI) protein and an antibiotic, the improvement comprising concurrently administering BPI protein product and ciprofloxacin in the treatment of a patient infected with a gram-negative bacteria selected from the group consisting of Pseudomonas, Enterobacter, and Acinetobacter species.
 3. In a method for enhancing the effect of antibiotic treatment of a patient infected with gram-negative bacteria by concurrently administering bactericidal/permeability-increasing (BPI) protein and an antibiotic, the improvement comprising concurrently administering BPI protein product and ofloxacin in the treatment of a patient infected with a gram-negative bacteria selected from the group consisting of Pseudomonas and Acinetobacter species.
 4. In a method for enhancing the effect of antibiotic treatment of a patient infected with gram-negative bacteria by concurrently administering bactericidal/permeability-increasing (BPI) protein and an antibiotic, the improvement comprising concurrently administering BPI protein product and aztreonam in the treatment of a patient infected with a gram-negative bacteria selected from the group consisting of Pseudomonas, Citrobacter, Enterobacter and Acinetobacter species.
 5. In a method for enhancing the effect of antibiotic treatment of a patient infected with gram-negative bacteria by concurrently administering bactericidal/permeability-increasing (BPI) protein and an antibiotic, the improvement comprising concurrently administering BPI protein product and imipenem in the treatment of a patient infected with a gram-negative bacteria selected from the group consisting of Enterobacter, Proteus, Providencia and Acinetobacter species.
 6. In a method for enhancing the effect of antibiotic treatment of a patient infected with gram-negative bacteria by concurrently administering bactericidal/permeability-increasing (BPI) protein and an antibiotic, the improvement comprising concurrently administering BPI protein product and gentamicin in the treatment of a patient infected with a gram-negative bacteria selected from the group consisting of Escherichia, Klebsiella, Edwardsiella, Salmonella, Pseudotnonas and Acinetobacter species.
 7. In a method for enhancing the effect of antibiotic treatment of a patient infected with gram-negative bacteria by concurrently administering bactericidal/permeability-increasing (BPI) protein and an antibiotic, the improvement comprising concurrently administering BPI protein product and amikacin in the treatment of a patient infected with a gram-negative bacteria selected from the group consisting of Pseudomonas, Xanthamonas, Escherichia, Proteus, Providencia, Morganella and Acinetobacter species.
 8. In a method for enhancing the effect of antibiotic treatment of a patient infected with gram-negative bacteria by concurrently administering bactericidal/permeability-increasing (BPI) protein and an antibiotic, the improvement comprising concurrently administering BPI protein product and tobramycin in the treatment of a patient infected with a gram-negative bacteria selected from the group consisting of Pseudomonas, Citrobacter, Serratia, Proteus and Acinetobacter species.
 9. In a method for enhancing the effect of antibiotic treatment of a patient infected with gram-negative bacteria by concurrently administering bactericidal/permeability-increasing (BPI) protein and an antibiotic, the improvement comprising concurrently administering BPI protein product and netilmicin in the treatment of a patient infected with a gram-negative bacteria selected from the group consisting of Acinetobacter species.
 10. In a method for enhancing the effect of antibiotic treatment of a patient infected with gram-negative bacteria by concurrently administering bactericidal/permeability-increasing (BPI) protein and an antibiotic, the improvement comprising concurrently administering BPI protein product and trimethoprim/sulfamethoxazole in the treatment of a patient infected with a gram-negative bacteria selected from the group consisting of Pseudomonas, Xanthamonas, Klebsiella, Enterobacter, Proteus and Acinetobacter species.
 11. In a method for enhancing the effect of antibiotic treatment of a patient infected with gram-negative bacteria by concurrently administering bactericidal/permeability-increasing (BPI) protein and an antibiotic, the improvement comprising concurrently administering BPI protein product and chloramphenicol in the treatment of a patient infected with a gram-negative bacteria selected from the group consisting of Enterobacter and Acinetobacter species.
 12. A method of treating a gram-negative bacterial infection in a subject comprising administering a BPI protein product and an antibiotic in synergistically effective amounts, wherein the antibiotic is selected from the group consisting of gentamicin, polymyxin B, cefamandole and ceftriaxone.
 13. The method of claim 12 wherein said antibiotic and said BPI protein product are administered in amounts where each would alone be bactericidally effective against a gram negative bacterial infection.
 14. The method of claim 12 wherein the antibiotic is gentarnicin and the gram-negative bacterial infection involves gram-negative bacteria selected from the group consisting of Escherichia, Klebsiella, Edwardsiella and Salmonella species.
 15. The method of claim 12 wherein the antibiotic is polymyxin B and the gram-negative bacterial infection involves gram-negative bacteria selected from the group consisting of Escherichia, Providencia and Pseudomonas species.
 16. The method of claim 12 wherein the antibiotic is cefamandole and the gram-negative bacterial infection involves Escherichia species.
 17. The method of claim 12 wherein the antibiotic is ceftriaxone and the gram-negative bacterial infection involves gram-negative bacteria selected from the group consisting of Pseudomonas, Enterobacter, Citrobacter, Klebsiella and Escherichia species.
 18. A method of killing gram-negative bacteria comprising administering a BPI protein product and an antibiotic in synergistically effective amounts, wherein the antibiotic is selected from the group consisting of gentamicin, polymyxin B, cefamandole and ceftriaxone.
 19. The method of claim 18 wherein the antibiotic is gentamicin and the gram-negative bacterial infection involves gram-negative bacteria selected from the group consisting of Escherichia, Klebsiella, Edwardsiella and Salmonella species.
 20. The method of claim 18 wherein the antibiotic is polymyxin B and the gram-negative bacterial infection involves gram-negative bacteria selected from the group consisting of Escherichia, Providencia and Pseudomonas species.
 21. The method of claim 18 wherein the antibiotic is cefamandole and the gram-negative bacterial infection involves Escherichia species.
 22. The method of claim 18 wherein the antibiotic is ceftriaxone and the gram-negative bacterial infection involves gram-negative bacteria selected from the group consisting of Pseudomonas, Enterobacter, Citrobacter, Klebsiella and Escherichia species.
 23. The method of claim 18 wherein said BPI protein product and said antibiotic are administered in vivo.
 24. The method of claim 18 wherein said BPI protein product and said antibiotic are administered in vitro.
 25. A pharmaceutical composition for treatment of gram-negative bacterial infection comprising a BPI protein product and an antibiotic in synergistically effective amounts, wherein the antibiotic is selected from the group consisting of gentamicin, polymyxin B, cefamandole and ceftriaxone.
 26. The pharmaceutical composition of claim 25 comprising a pharmaceutically-acceptable diluent, adjuvant, or carder.
 27. In a method for treating a patient infected with a Pseudomonas gram-negative bacterial species that is resistant to an antibiotic selected from the group consisting of amikacin, aztreonam, cefazolin, cefoxitin, ceftriaxone, cefuroxime, ofloxacin, piperacillin and ticarcillin, the improvement comprising the step of concurrently administering the antibiotic and an amount of BPI protein product effective to reverse the resistance of the gram-negative bacterial species to the antibiotic.
 28. In a method for treating a patient infected with a Xanthamonas gram-negative bacterial species that is resistant to an antibiotic selected from the group consisting of amikacin, piperacillin and trimethoprim/sulfamethoxazole, the improvement comprising the step of concurrently administering the antibiotic and an amount of BPI protein product effective to reverse the resistance of the gram-negative bacterial species to the antibiotic.
 29. In a method for treating a patient infected with a Escherichia gram-negative bacterial species that is resistant to an antibiotic selected from the group consisting of cefazolin and ceftriaxone, the improvement comprising the step of concurrently administering the antibiotic and an amount of BPI protein product effective to reverse the resistance of the gram-negative bacterial species to the antibiotic.
 30. In a method for treating a patient infected with a Klebsiella gram-negative bacterial species that is resistant to an antibiotic selected from the group consisting of trimethoprim/suifamethoxazole and ceftriaxone, the improvement comprising the step of concurrently administering the antibiotic and an amount of BPI protein product effective to reverse the resistance of the gram-negative bacterial species to the antibiotic.
 31. In a method for treating a patient infected with a Citrobacter gram-negative bacterial species that is resistant to ceftriaxone antibiotic, the improvement comprising the step of concurrently administering the antibiotic and an amount of BPI protein product effective to reverse the resistance of the gram-negative bacterial species to the antibiotic.
 32. In a method for treating a patient infected with a Enterobacter gram-negative bacterial species that is resistant to an antibiotic selected from the group consisting of ampicillin, aztreonam, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, piperacillin, ticarcillin, azlocillin, carbenicillin, cefamandole and cefonicid, the improvement comprising the step of concurrently administering the antibiotic and an amount of BPI protein product effective to reverse the resistance of the gram-negative bacterial species to the antibiotic.
 33. In a method for treating a patient infected with a Serratia gram-negative bacterial species that is resistant to an antibiotic selected from the group consisting of cefotaxime and ceftazidime, the improvement comprising the step of concurrently administering the antibiotic and an amount of BPI protein product effective to reverse the resistance of the gram-negative bacterial species to the antibiotic.
 34. In a method for treating a patient infected with a Providencia gram-negative bacterial species that is resistant to an antibiotic selected from the group consisting of cefazolin and cefuroxime, the improvement comprising the step of concurrently administering the antibiotic and an amount of BPI protein product effective to reverse the resistance of the gram-negative bacterial species to the antibiotic.
 35. In a method for treating a patient infected with a Acinetobacter gram-negative bacterial species that is resistant to an antibiotic selected from the group consisting of amikacin, ampicillin, aztreonam, cefazolin, cefotaxime, cefoxitin, cefiazidime, ceftriaxone, cefuroxime, ciprofloxacin, gentamicin, piperacillin, ticarcillin, trimethoprim/sulfamethoxazole, amoxicillin, carbenicillin, cefamandole, cefonicid, cefoperazone, cefotetan, ceftizoxime, chloramphenicol, mezlocillin and netilmicin, the improvement comprising the step of concurrently administering the antibiotic and an amount of BPI protein product effective to reverse the resistance of the gram-negative bacterial species to the antibiotic.
 36. The method of any one of claims 1 through 35 wherein the BPI protein product is an N-terminal fragment with a molecular weight of approximately 21 to 25 kD, or a dimeric form thereof.
 37. The method of any one of claims 1 through 35 wherein the BPI protein product is rBPI₂₃, rBPI₂₁, or rBPI₅₀. 